A glomerular filtration rate of less than 15 ml/min is classified as stage 5 (G5), indicating that the renal disease is end-stage and the initiation of replacement therapy should be considered (option 2 true, option 1 false). In this situation, good glycemic control is not expected to reverse renal damage, although it may help to delay progression (false choice 3). These patients usually present stage A3 albuminuria (above 300 mg/24 h), and may reach the nephrotic range (false choice 4).

A glomerular filtration rate of less than 15 ml/min is classified as stage 5 (G5), indicating that the renal disease is end-stage and the initiation of replacement therapy should be considered ([HIDDEN]). In this situation, good glycemic control is not expected to reverse renal damage, although it may help to delay progression ([HIDDEN]). These patients usually present stage A3 albuminuria (above 300 mg/24 h), and may reach the nephrotic range ([HIDDEN]).

A 67-year-old woman with chronic kidney disease secondary to diabetic nephropathy. She currently has a creatinine of 3.2 mg/dL with estimated glomerular filtration rate (CKD-EPI) 14 ml/min. Which of the following is true?

He presents stage 3 chronic kidney disease and should initiate phosphorus chelators.

He has stage 5 chronic kidney disease and renal replacement therapy should be considered.

Good glycemic control can reverse renal failure.

It is unlikely to present proteinuria higher than 500 mg/24 h.

Kidney failure

Diagnostic approach Measurement for CKD Stages of kidney failure Chronic kidney failure is measured in five stages, which are calculated using the person's GFR, or glomerular filtration rate. Stage 1 CKD is mildly diminished renal function, with few overt symptoms. Stages 2 and 3 need increasing levels of supportive care from their medical providers to slow and treat their renal dysfunction. People with stage 4 and 5 kidney failure usually require preparation towards active treatment in order to survive. Stage 5 CKD is considered a severe illness and requires some form of renal replacement therapy (dialysis) or kidney transplant whenever feasible. Glomerular filtration rate

Diabetic nephropathy

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. Protein loss in the urine due to damage to the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) and result in the nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

Chronic kidney disease

It may also be useful at an earlier stage (e.g. CKD3) when urine albumin-to-creatinine ratio is more than 30 mg/mmol, when blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular disorder or secondary disease amenable to specific treatment. Other benefits of early nephrology referral include proper education regarding options for kidney replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those people with chronic kidney disease opting for future hemodialysis. Renal replacement therapy At stage 5 CKD, kidney replacement therapy is usually required, in the form of either dialysis or a kidney transplant.

Dialysis

In medicine, dialysis (from Greek διάλυσις, dialysis, "dissolution"; from διά, dia, "through, and λύσις, lysis, "loosening or splitting") is the process of removing excess water, solutes, and toxins from the blood in people whose kidneys can no longer perform these functions naturally. This is referred to as renal replacement therapy. The first successful dialysis was performed in 1943. Dialysis may need to be initiated when there is a sudden rapid loss of kidney function, known as acute kidney injury (previously called acute renal failure), or when a gradual decline in kidney function chronic kidney disease reaches stage 5. Stage 5 chronic renal failure is reached when the glomerular filtration rate is 10–15% of normal, creatinine clearance is less than 10 mL per minute and uremia is present.

Glomerular filtration rate

The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a "T" to patients who have had a transplant regardless of stage.

Kidney failure

Causes of acute kidney failure include low blood pressure, blockage of the urinary tract, certain medications, muscle breakdown, and hemolytic uremic syndrome. Causes of chronic kidney failure include diabetes, high blood pressure, nephrotic syndrome, and polycystic kidney disease. Diagnosis of acute failure is often based on a combination of factors such as decreased urine production or increased serum creatinine. Diagnosis of chronic failure is based on a glomerular filtration rate (GFR) of less than 15 or the need for renal replacement therapy. It is also equivalent to stage 5 chronic kidney disease.

InternalMed_Harrison

FIGURE 419-3 Time course of development of diabetic nephropathy. The relationship of time from onset of diabetes, the glomerular filtration rate (GFR), and the serum creatinine are shown. (Adapted from RA DeFranzo, in Therapy for Diabetes Mellitus and Related Disorders, 3rd ed. American Diabetes Association, Alexandria, VA, 1998.) 2426 Improved glycemic control reduces the rate at which microalbuminuria appears and progresses in type 1 and type 2 DM. However, once macroalbuminuria is present, it is unclear whether improved glycemic control will slow progression of renal disease. During the later phase of declining renal function, insulin requirements may fall as the kidney is a site of insulin degradation. As the GFR decreases with progressive nephropathy, the use and dose of glucose-lowering agents should be reevaluated (see Table 418-5). Some glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency. Many individuals with type 1

Assessment of kidney function

The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease. Chronic kidney disease stages Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking. For most patients, a GFR over 60 (mL/min)/(1.73 m2) is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.

Large kidneys predict poor renal outcome in subjects with diabetes and chronic kidney disease.

Renal hypertrophy occurs early in diabetic nephropathy, its later value is unknown. Do large kidneys still predict poor outcome in patients with diabetes and Chronic Kidney Disease (CKD)? Seventy-five patients with diabetes and CKD according to a Glomerular Filtration Rate (GFR, by 51Cr-EDTA clearance) below 60 mL/min/1.73 m2 or an Albumin Excretion Rate above 30 mg/24 H, had an ultrasound imaging of the kidneys and were cooperatively followed during five years by the Diabetology and Nephrology departments of the Centre Hospitalier Universitaire de Bordeaux. The patients were mainly men (44/75), aged 62 +/- 13 yrs, with long-standing diabetes (duration:17 +/- 9 yrs, 55/75 type 2), and CKD: initial GFR: 56.5 (8.5-209) mL/min/1.73 m2, AER: 196 (20-2358) mg/24 H. Their mean kidney lenght (108 +/- 13 mm, 67-147) was correlated to the GFR (r = 0.23, p < 0.05). During the follow-up, 9/11 of the patients who had to start dialysis came from the half with the largest kidneys (LogRank: p < 0.05), despite a 40% higher initial isotopic GFR. Serum creatinine were initially lower (Small kidneys: 125 (79-320) micromol/L, Large: 103 (50-371), p < 0.05), but significantly increased in the "large kidneys" group at the end of the follow-up (Small kidneys: 129 (69-283) micromol/L, Large: 140 (50-952), p < 0.005 vs initial). The difference persisted in the patients with severe renal failure (KDOQI stages 4,5). Large kidneys still predict progression in advanced CKD complicating diabetes. In these patients, ultrasound imaging not only excludes obstructive renal disease, but also provides information on the progression of the renal disease.

Diabetic nephropathy

It is recommended that diabetics have their albumin levels checked annually, beginning immediately after a diagnosis of type 2 diabetes and five years after a diagnosis of type 1 diabetes. Medical imaging of the kidneys, generally by ultrasonography, is recommended as part of a differential diagnosis if there is suspicion of urinary tract obstruction, urinary tract infection, kidney stones or polycystic kidney disease. Conformation kidney biopsy should only be performed if non-diabetic kidney disease is suspected. Urine analysis in patients with diabetic kidney disease is often bland. In cases of severely increased microalbuminuria, hematuria might be present. fat bodies might be present in patients who develop nephrotic-range proteinuria. Staging To stage the degree of damage in this (and any) kidney disease, the serum creatinine is determined and used to calculate the estimated glomerular filtration rate (eGFR). Normal eGFR is equal to or greater than 90ml/min/1.73 m2.

Chronic kidney disease

Stage 3: Moderate reduction in GFR (30–59 ml/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral. Stage 4: Severe reduction in GFR (15–29 ml/min/1.73 m2) Preparation for kidney replacement therapy. Stage 5: Established kidney failure (GFR <15 ml/min/1.73 m2), permanent kidney replacement therapy, or end-stage kidney disease.

Chronic kidney disease

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. Initially there are generally no symptoms; later, symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications include an increased risk of heart disease, high blood pressure, bone disease, and anemia. Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Risk factors include a family history of chronic kidney disease. Diagnosis is by blood tests to measure the estimated glomerular filtration rate (eGFR), and a urine test to measure albumin. Ultrasound or kidney biopsy may be performed to determine the underlying cause. Several severity-based staging systems are in use.

Assessment of kidney function

The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria 1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2) 4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2) 5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2) Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a "T" to patients who have had a transplant regardless of stage.

Kidney transplantation

Indications The indication for kidney transplantation is end-stage renal disease (ESRD), regardless of the primary cause. This is defined as a glomerular filtration rate below 15 ml/min/1.73 m2. Common diseases leading to ESRD include renovascular disease, infection, diabetes mellitus, and autoimmune conditions such as chronic glomerulonephritis and lupus; genetic causes include polycystic kidney disease, and a number of inborn errors of metabolism. The commonest 'cause' is idiopathic (i.e. unknown).

Kidney

Kidney injury and failure Generally, humans can live normally with just one kidney, as one has more functioning renal tissue than is needed to survive. Only when the amount of functioning kidney tissue is greatly diminished does one develop chronic kidney disease. Renal replacement therapy, in the form of dialysis or kidney transplantation, is indicated when the glomerular filtration rate has fallen very low or if the renal dysfunction leads to severe symptoms. Dialysis

Continuously evolving management concepts for diabetic CKD and ESRD.

During the past 50 years, a global pandemic of kidney failure attributed to diabetes mellitus provoked continuously changing treatment strategies based in the belief that micro- and macrovascular complications of diabetes may be preventable. Both patient and physician have revised, and sometimes reversed drug regimens based on inferences extracted from prospective, controlled, properly populated trials. Illustrating this dilemma is a newly relaxed target for glycosylated hemoglobin (HbA1c) of 7%, introduced because of the greater rate of cardiovascular complications noted when striving to reduce attained HbA1c to < or = 6.5%. Our concept of the natural history of kidney disease in diabetes has repeatedly been modified by a rising mean age of those developing uremia (now 64.5 years). Underscoring the reality that the majority of diabetic kidney failure patients fall within the geriatric age group. An encouraging finding first reported in 2005 and continuing through 2009 is a declining incidence rate of irreversible advanced kidney failure in individuals known to have diabetes. That this "good news" results from appropriate renoprotective treatment is as yet unsubstantiated wishful thinking.

Mesoamerican nephropathy

Suspected disease: Estimated GFR (eGFR) < 60 ml/min/1.73m2 Absence of diabetes, hypertension, autoimmune disease, glomerular disease, congenital kidney disease, obstructive kidney disease as a clear cause of kidney disease (these comorbidities may be present but cannot account for disease development) Residing in a hotspot region Proteinuria < 2g/24h or 2g/g urine creatinine Likely disease: All of the above, plus eGFR < 60 ml/min/1.73m2 on 3 month or longer repeat measurement Relative hypokalemia and/or hyperuricemia Kidney ultrasound with loss of corticomedullary differentiation or bilateral small kidney size, without cystic disease or large stone burden Kidney biopsy showing primary tubulointerstitial disease without alternative cause of kidney disease in evidence

Secondary hyperparathyroidism

Extended Release Calcifediol was recently approved by the FDA as a treatment for secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and low vitamin D blood levels (25-hydroxyvitamin D less than 30 ng/mL). It can help treat SHPT by increasing Vitamin D levels and lowering parathyroid hormone or PTH. It is not indicated for people with stage 5 CKD or on dialysis. In the treatment of secondary hyperparathyroidism due to chronic kidney disease on dialysis calcimimetics do not appear to affect the risk of early death. It does decrease the need for a parathyroidectomy but caused more issues with low blood calcium levels and vomiting. Most people with hyperparathyroidism secondary to chronic kidney disease will improve after renal transplantation, but many will continue to have a degree of residual hyperparathyroidism (tertiary hyperparathyroidism) post-transplant with associated risk of bone loss, etc.

Glomerular filtration rate

The CKD-EPI equation performed better than the MDRD (Modification of Diet in Renal Disease Study) equation, especially at higher GFR, with less bias and greater accuracy. When looking at NHANES (National Health and Nutrition Examination Survey) data, the median estimated GFR was 94.5 mL/min per 1.73 m2 vs. 85.0 mL/min per 1.73 m2, and the prevalence of chronic kidney disease was 11.5% versus 13.1%. Despite its overall superiority to the MDRD equation, the CKD-EPI equations performed poorly in certain populations, including black women, the elderly and the obese, and was less popular among clinicians than the MDRD estimate. The CKD-EPI equation is: where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is −0.329 for females and −0.411 for males, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.

Delayed progression to dialysis with early and intensive management of predialysis chronic kidney disease: a case-based approach.

In addition to hypertension and diabetes, disorders in mineral metabolism and bone disease (e.g. affecting phosphorus, calcium, parathyroid hormone, and vitamin D) are common complications of chronic kidney disease (CKD) and contribute to morbidity and mortality. Consequently, CKD requires multifactorial treatment to slow CKD progression and avoid end-stage renal disease. CKD progression and treatment outcomes are monitored by measuring the estimated glomerular filtration rate (eGFR), which decreases by 2-12 ml/min/1.73 m(2) per year depending on the stage of CKD and comorbidities, such as diabetes. This paper presents representative case studies illustrating the delay and reversal of CKD progression with comprehensive, individualized treatment regimens, including non-calcium phosphate binders, antihypertensives, lipid-lowering drugs, calcimimetics, and other drugs as required, to treat each component of CKD including CKD-mineral and bone disorder. Four patients are included, with an average age of 70-81 years and CKD stage 3 or 4 accompanied by various comorbidities, most notably diabetes and hypertension. The range of treatment and follow-up durations was 6-7 years. In each case, there was evidence of slowing or prevention of CKD progression, according to eGFR and serum creatinine, regardless of the patient's age or CKD stage. Despite a baseline eGFR of <20 ml/min/1.73 m(2) in 1 female patient, after 6 years of follow-up, her eGFR had stabilized and was maintained at >15 ml/min/1.73 m(2). These observations reinforce the value of early nephrology referral and comprehensive management of CKD and underlying conditions (hypertension and diabetes) beginning at eGFR <60 ml/min/1.73 m(2).

Glomerular filtration rate

Modification of Diet in Renal Disease (MDRD) formula Another formula for calculating the GFR is the one developed by the Modification of Diet in Renal Disease Study Group. Most laboratories in Australia, and the United Kingdom now calculate and report the estimated GFR along with creatinine measurements and this forms the basis of diagnosis of chronic kidney disease. The adoption of the automatic reporting of MDRD-eGFR has been widely criticised. The most commonly used formula is the "4-variable MDRD", which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease; however, both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have not been validated in acute renal failure. For creatinine in μmol/L: For creatinine in mg/dL:

[Diabetic Kidney Disease 3rd stage - laboratory markers of mineral bone disorder].

Diabetes mellitus is the most common cause of end stage kidney disease in the developed countries. Chronic kidney disease-mineral and bone disorder (CKD-MBD) develops with deteriorating of the renal functions. Diabetic patients on hemodialysis are characterized by low bone turnover, higher prevalence of severe and progressive vascular calcification with increased cardiovascular morbidity and mortality. The main factor which causes vascular calcification in patients with diabetic kidney disease (DKD) is poor glycemic control. The recent trial findings describe an inverse correlation between intact parathyroid hormone (iPTH) serum levels and glycemic control in a group of diabetic patients on hemodialysis. The objective of the proposed project is to access the difference of the laboratory markers MBD in the group of patients with 3rd stage DKD depending on glycemic control. We focused on the relationship between the glycemic compensation of diabetes (HbA1c) and iPTH serum level. Ninety one patients with 3rd stage DKD were investigated. There were 46 women (50.5 %) and 45 men (49.5 %), average age of patients was 71.2 ± 7.0 years, with creatinine level 128 ± 30 μmol/l and estimated glomerular filtration (eGF, MDRD) 0.82 ± 0.16 ml/s. There were 60 patients with better glycemic control of diabetes (HbA1c < 7 %) vs 29 patients with poorly controlled diabetes (HbA1c > 7 %). MBD markers were compared in both groups. Patients were further stratified into subgroups based on the serum level of iPTH (iPTH < 35 pg/ml vs iPTH > 35 pg/ml) and MBD markers compared. Statistical analysis was performed using and Mann-Whitney test. We have found the statistical significance in the serum phosphate and proteinuria levels in between groups with HbA1c < 7 % vs patients with HbA1c > 7 %. Diabetics with better glycemic control had significant reduction in serum phosphate level (1.14 ± 0.20 vs 1.23 ± 0.18 mmol/l, p = 0.038) and in 24 hrs proteinuria level (0.56 ± 1.35 vs 1.30 ± 1.61 g/day, p = 0.007). In the group of presumed low bone turnover (iPTH < 35 pg/ml) we have found the trend towards increased serum calcium level (2.49 ± 0.12 vs 2.43 ± 0.10 mmol/l, p = 0.063) and increased HbA1c value (7.5 ± 1.8 vs 6.4 ± 1.6 %, p = 0.023). Our results suggest the closer relationship between glycemic control of diabetes and mineral-bone disorder in earlier stages of DKD. diabetes mellitus type 2 (DM2T) - chronic kidney disease (CKD) - mineral and bone disorder (MBD).

Phosphate nephropathy

Diagnosis Phosphate nephropathy can be diagnosed via different types of assessment, most of which are also used to detect acute kidney injury and chronic kidney disease. Most phosphate nephropathy incidents are diagnosed weeks or months after taking OSP, due to its clinical silence. For example, these assessments include the measurement of serum phosphorus with an elevation of more than 3 mmol/L, the finding of an elevated serum creatinine level and a decrease in glomerular filtration rate (GFR), urine microscopy for crystallization detection, the image of calcium phosphate crystals deposited through CT scanning, urinalysis, renal biopsy specimens with histochemical staining for calcium phosphate. These assessments are generally carried out within the laboratory environment, in which longer waiting time is required to attain the results.

Effect of glycemic control on intact parathyroid hormone level in end stage renal disease patients on maintenance hemodialysis.

We evaluated the relationship between iPTH levels and glycemic control in patients with diabetes and end stage renal disease (ESRD) on maintenance hemodialysis (MHD). The study included 98 subjects with ESRD and type 2 diabetes aged 30-75 years who were on MHD. These were divided into two groups--patients with HbA1c >7.0 (53 mmol/mol) (poor glycemic control group) and patients with HbA1c <7.0 (53 mmol/mol) (good glycemic control group). All patients had been on regular bicarbonate haemodialysis for more than 6 months using polysulfone membrane dialyzer; 4 h per episode 3 times/week, with a dialysis fluid of 3.0 mEq/L of calcium concentration. 1-α-(OH)D3 and calcium carbonate were used routinely in all patients. The contribution of each relevant biological parameter to serum iPTH level was assessed using multiple regression test. Poor glycemic control was associated with reduced serum iPTH level and good glycemic control with higher serum iPTH. The serum HbA1c level was significantly correlated with the serum iPTH level (p=0.0003). Glycemic control is a significant determinant of iPTH level in diabetic ESRD patients on MHD.

Glomerular filtration rate

A common mistake made when just looking at serum creatinine is the failure to account for muscle mass. Hence, an older woman with a serum creatinine of 1.4 mg/dL may actually have a moderately severe chronic kidney disease, whereas a young muscular male can have a normal level of renal function at this serum creatinine level. Creatinine-based equations should be used with caution in cachectic patients and patients with cirrhosis. They often have very low muscle mass and a much lower creatinine excretion rate than predicted by the equations below, such that a cirrhotic patient with a serum creatinine of 0.9 mg/dL may have a moderately severe degree of chronic kidney disease. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.

[Current therapy of chronic renal failure].

The course of chronic renal failure is generally progressive and mediated by several factors that operate in combination. Several extrarenal events which may cause transient or permanent deterioration of renal function, are important, because their correction may slow the progression of renal disease e.g. volume disorders, infection, nephrotoxic agents. In progression of chronic renal disease leading factors are hypertension, proteinuria and high protein/phosphorus intake. Number of evidence suggests that ameliorating hypertension, reducing proteinuria slow the progression of chronic renal failure. Clinical studies in diabetic nephropathy demonstrated that the renoprotective effect of ACE inhibitors was independent of their effect of systemic blood pressure. In ESRD patients access for renal replacement therapy should be obtained as early as possible. An A-V fistula may take several weeks to mature especially in diabetic or elderly patients. Early dialysis has been advocated in diabetic patients. In general, patients can start ESRD therapy when residual kidney function drops to 5-10% of normal value. High quality of dialysis should be provided to the uremic patient with respect of successful renal transplantation.

Survival of patients on maintenance haemodialysis over a twenty-year period.

Patient survival is a key index of the overall adequacy of treatment in most chronic diseases. Analyses of survival of patients undergoing haemodialysis is very important, as it may offer clues and ideas for prolonging survival of patients with end-stage renal disease (ESRD). The aims of this study were to describe the characteristics of the patients on maintenance haemodialysis therapy over a period of 20 years, to determine the survival rate of these patients according to ages at the onset of haemodialysis, the primary renal diseases, and the cause of death, and to determine the survival rate at five, ten, fifteen and twenty years of haemodialysis treatment at our centre. The charts of 518 unselected patients, 282 male and 236 female, treated with maintenance haemodialysis therapy in a period of 20 years (1985-2005) were reviewed. At the time of evaluation, 164 patients were currently being treated, and 354 patients overall had been diseased. Statistical analysis was performed to evaluate the relationship between survival and patient characteristics such as age, gender, primary renal disease, and age at dialysis onset. Actual survival rates were determined by the Kaplan-Meier method. The survival rate of our patients treated with maintenance haemodialysis was 60% at 5 years, 37% at 10 years, 25% at 15 years and 9% at 20 years. Female patient survival was superior to male. Patients aged under 40 at the start of dialysis had a better survival probability compared to older patients. Patients with diabetes mellitus and nephroangiosclerosis, had a lower survival rate compared to patients with glomerulonephritis and with adult dominant polycystic kidney disease. Cardiac death was the most common cause of death in patients involved in the study. About 52% of the patients died from cardiovascular disease. Death is the most severe consequence of inadequate dialysis and can be used as an index of the adequacy of the dialysis therapy. Treatment factors that may improve outcomes include an early start of dialysis therapy, a high dose of dialysis (Kt/V over 1.2), correction of anemia, adequate protein and caloric intake, control of calcium and phosphate metabolism, and the use of biocompatible dialyzers.

Early referral to a nephrologist is associated with better outcomes in type 2 diabetes patients with end-stage renal disease.

End-stage renal disease (ESRD) requiring renal replacement therapy (RRT) is a late complication of type 2 diabetes. The correlation between pre-ESRD medical care and outcome has been rarely studied in France. Community-based study of case-incIdent ESRD patients. Medical care practices were described retrospectively when starting RRT. Medical status, mortality, morbIdity, and quality-of-life were recorded prospectively. One hundred and fourty-eight ESRD patients with type 2 diabetes were included. Factors independently correlated with mortality within 3 Months of RRT onset were presence of physical impairment of ambulation at onset of RRT [odd ratio (OR): 5, (95%CI: 1.9-13.3)], and starting RRT in life-threatening circumstances [OR: 3.6, (95%CI: 1.2-10.7)]. Factors independently correlated with "poor outcome" 1 Year after the onset of RRT were BMI less than 20 kg/m2 [OR: 13.4, (95%CI: 1.5-120.2)] and presence of 2 [OR: 2.7, (95%CI: 0.9-8.4)], or 3 or more comorbId conditions [OR: 4, (95% CI: 1.4-11)]. Three Months after the first RRT session, survival was 16.4% better for patients who had had regular nephrological care versus none, and 9.1% better for those who had had late nephrological care versus none. Type 2 diabetes patients starting RRT in an emergency setting had had significant less regular nephrological care. Length of their first hospital stay was significantly longer. They were more likely to have lower resIdual renal function, gastrointestinal symptoms, lower serum albumin, lower hematocrit, lower serum calcium, and higher serum phosphorus. During the course of chronic renal failure in type 2 diabetes patients, early implementation of nephrological well-established guIdelines is associated with better outcome after starting RRT.

Kidney

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. The global estimated prevalence of CKD is 13.4%, and patients with kidney failure needing renal replacement therapy are estimated between 5 and 7 million. Procedures used in the management of kidney disease include chemical and microscopic examination of the urine (urinalysis), measurement of kidney function by calculating the estimated glomerular filtration rate (eGFR) using the serum creatinine; and kidney biopsy and CT scan to evaluate for abnormal anatomy. Dialysis and kidney transplantation are used to treat kidney failure; one (or both sequentially) of these are almost always used when renal function drops below 15%. Nephrectomy is frequently used to cure renal cell carcinoma.

The current state of chronic dialysis treatment in Japan (as of December 31, 2000).

The annual statistical survey conducted at the end of 2000 by the Japanese Society for Dialysis Therapy collected responses from 3358 (99.94%) of 3360 institutions. Japan's total dialysis patient population at the end of the year 2000, as identified by this survey, was 206,134, an increase of 8921 (4.5%) over 1999. This translates to 1624.1 patients per million population. The annual crude mortality rate was 9.4% for the period starting at the end of the year 1999 and ending at the end of the year 2000. The mean patient age at the initiation of dialysis treatment was 63.8 (+/- 13.9; +/- SD) years; the mean age of the overall dialysis patient population was 61.2 years (+/- 13.3). Both these mean ages, which had been increasing since 1983, again continued to increase. Among the primary diagnosis, the prevalence of diabetic nephropathy had continued to increase again since 1999, to 36.6%, whereas that of chronic glomerulonephritis had continued to decline, down to 32.5%, during the same one-year period since the 1999 survey. The 2000 years-end survey incorporated the following additional variables for the first time: usage of oral antihypertensives, pre- and post-dialysis systolic and diastolic blood pressures, serum HDL cholesterol level, types and dosage of oral Vitamin D analogs administered, dosage of oral calcium carbonate administered, history of intervention for peripheral vascular disease (bypass surgery, synthetic graft replacement, stenting), history of coronary artery bypass grafting (CABG), history of percutaneous transluminal coronary angioplasty (PTCA), whether stenting had been previously performed for the treatment of ischemic heart disease, number of cigarettes smoked, the type of vascular access used at the initiation of dialysis, and the year and month the vascular access was created. The survey results indicate that 60.9% of the total dialysis patient population was using oral antihypertensives. The patients' mean serum HDL cholesterol level was 47.65 +/- 18.47 mg/dL, showing positive correlation with serum albumin level and reverse correlation with body mass index. 1.6% of all dialysis patients had previously undergone amputation, and 0.7% had a history of bypass surgery for peripheral vascular disorder. 4.5% of hemodialysis patients had a history of cardiac infarction, 1.6% had previously undergone CABG, and 2.8%, PTCA. At the time the survey was conducted, 2.0% of all dialysis patients were undergoing oral Vitamin D analog pulse therapy, and 6% were undergoing intravenous Vitamin D analog pulse therapy. A history of amputation, myocardial infarction, cerebral infarction, and cerebral bleeding were identified as high-risk factors of vital prognosis. Additionally, high mortality risk was associated with the following: glutamic-pyruvic transaminase levels exceeding 20 IU/L; positive HCV antibody status; comorbid conditions such as hepatic cell carcinoma and liver cirrhosis; platelet counts below 100,000/mL or equal to or greater than 200,000/mL; C-reactive protein levels of 0.2 mg/dL and higher, leukocyte counts of less than 3000/mL or equal to or greater than 8000/mL; and body mass index of below 22 kg/m2, as well as total serum cholesterol levels of below 160 mg/dL or equal to or greater than 260 mg/dL.

Clinical features of patients treated by peritoneal dialysis for over a decade.

Peritoneal dialysis (PD) is well-established as renal replacement therapy in end stage renal disease and has survival rates similar or better than hemodialysis (HD) for the initial years on dialysis therapy. However retention rate is lower due to higher technique failure rates than in HD and few patients stay on PD for more than 10 years (PD10 yrs</sub). Here we investigated clinical features characterizing PD10 yrs</sub patients. In a single center study of 450 prevalent PD patients, 35 PD10 yrs</sub patients (n=35) were compared with patients (n=415) who had been on PD for shorter periods of time in terms of clinical characteristics. Peritoneal transport, blood pressure, solute clearance, nutrition status, and blood calcium, phosphate and parathyroid hormone levels were measured dialysis start and, in PD10 yrs</sub patients, also after 5 and 10 years of PD. The PD10 yrs</sub patients differed from the other PD patients in that (1) the proportion of women was higher; (2) body mass index (BMI) was lower; (3) there was no patient with diabetic nephropathy as primary diagnosis; (4) the incidence of peritonitis was lower; (5) glomerular filtration rate was higher; and (6) parathyroid hormone (PTH) levels were lower in those with decade-long PD treatment. In PD10 yrs</sub patients, serum albumin was maintained at a high level throughout the 10 year follow up; hemoglobin levels after 5 and 10 years of PD were higher than at the beginning of the treatment; blood calcium and phosphate concentrations were maintained at acceptable levels; while the dialysate/plasma ratio of creatinine, D/<iP</i-value, increased during the decade-long PD treatment. Patients receiving PD10 years</sub had lower incidence of peritonitis, lower BMI, adequate control of blood calcium and phosphate levels and solute clearance, and were more often women than PD patients treated for shorter periods of time.

Xipamide

Unlike with thiazides, only terminal kidney failure renders xipamide ineffective. Uses Xipamide is used for cardiac oedema caused by decompensation of heart failure renal oedema, chronic renal disease (but not with anuria) hepatic oedema caused by cirrhosis ascites lymphoedema hypertension in combination with chronic renal disease Pharmacokinetics After oral administration, 20 mg of xipamide are resorbed quickly and reach the peak plasma concentration of 3 mg/l within an hour. The diuretic effect starts about an hour after administration, reaches its peak between the third and sixth hour, and lasts for nearly 24 hours. One third of the dose is glucuronidized, the rest is excreted directly through the kidney (1/3) and the faeces (2/3). The total plasma clearance is 30-40 ml/min. Xipamide can be filtrated by haemodialysis but not by peritoneal dialysis. Dosage Initially 40 mg, it can be reduced to 10–20 mg to prevent a relapse.


An increase in indirect bilirubin less than 5 (intermittently, under stress) in a young healthy boy should make us think of Gilbert's syndrome. In Rotor syndrome, Dubin-Johnson syndrome and choledocholithiasis there is an increase in direct bilirubin. In the case of acute hepatitis there should be an elevation of transaminases.

A 17-year-old boy, athletic and with no history of interest, comes to the doctor for occasional conjunctival jaundice. He denies drug intake and abdominal pain. Laboratory tests show normal ALT, AST, GGT and FA, with total bilirubin of 3.2 mg/dl and direct bilirubin of 0.4 mg/dl. She has no anemia and the liver is ultrasonographically normal. What is her diagnosis?

Cases from the Osler Medical Service at Johns Hopkins University.

A 37-year-old woman presented with increasing abdominal pain and jaundice. Six weeks before admission, she developed persistent diarrhea and jaundice of the skin. She also bruised easily, and her gums bled. In the subsequent weeks, her appetite decreased, she was fatigued, and she had nausea, vomiting, and abdominal distension. She had a history of drinking 1 quart of vodka every day for 20 years, with brief periods of abstinence; she stopped consuming alcohol 11 days before admission because it no longer provided symptomatic relief. Her past medical history was also notable for depression, including a suicide attempt 4 years earlier. She did not smoke, use illicit drugs, or have unprotected sexual intercourse. She had received no blood transfusions and had not traveled recently. She took no medications, except for occasional ibuprofen. On physical examination, she was thin and deeply jaundiced, and she trembled and responded slowly to questions. She was afebrile but tachypneic, and she had orthostatic hypotension. Her HEENT examination was notable for scleral and sublingual icterus, as well as crusted blood on her gums and teeth. The jugular veins were flat. The cardiac examination revealed tachycardia (heart rate, 103 beats per minute) without murmurs, rubs, or gallops. The abdomen was nontender and protuberant, with hypoactive bowel sounds; the spleen was not palpable, and there was no fluid wave or caput medusae. The liver percussed to 18 cm, with a smooth edge extending 10 cm below the costal margin. She had cutaneous telangiectases on her chest and bilateral palmar erythema. There was no peripheral edema. The neurologic examination was notable for asterixis. Her stool was guaiac positive. Laboratory studies revealed the following values: hematocrit, 21.2%; white blood cells, 17,310/mm(3); ammonia, 42 micromol/L; serum creatinine, 3.9 mg/dL; serum urea nitrogen, 70 mg/dL; albumin, 2.1 g/dL; total bilirubin, 26.8 mg/dL; alanine aminotransferase, 14 U/L; aspartate aminotransferase, 77 U/L; alkaline phosphatase, 138 U/L; prothrombin time, 103 seconds (international normalized ratio, 10.6); and urinary sodium, <5 mg/dL. Urinalysis revealed an elevated specific gravity and numerous muddy granular casts. Hepatitis A, B, and C serologies were negative. On abdominal ultrasound examination, there was no ascites, and the liver was echogenic. The portal and hepatic veins were patent, and the hepatic arteries were normal. The spleen measured 14 cm. What is the diagnosis?

Rotor Syndrome Presenting as Dubin-Johnson Syndrome.

A 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease. Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile. Abdominal ultrasound was unremarkable. A panel of chronic liver diseases was negative except for increased serum (147.4 μg/dL) and urinary (179 μg/24 h) copper, with normal ceruloplasmin. No other Leipzig criteria for Wilson's disease were found, including a negative test for <iATP7B</i gene mutations (by exome sequencing). Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output). Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the <iABBC2</i gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G - p.Lys495Glu). Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4-16 of <iSLCO1B3</i gene (encoding OATP1B3) and all <iSLCO1B1</i exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis. Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired hepatic bilirubin excretion), respectively. We report a case of compound hereditary hyperbilirubinemia with a misleading presentation with special focus on its diagnosis, particularly the advantage of extensive unbiased genetic testing by dedicated laboratories. With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures.

[Utility of analytical parameters in the diagnosis of liver disease].

Liver function tests include biochemical parameters (AST, ALT, GGT or Alkaline phosphatase), bilirubin and albumin levels and coagulation tests as prothrombin activity. These tests are commonly used in the routine screening even in symptomatic as in asymptomatic patients, and the right evaluation of the results is of vital importance. Cytolytic elevation in serum aminotransferases: In mild chronic elevation pharmacological toxicity, viral hepatitis, alcoholic and non-alcoholic fatty liver disease and hemochromatosis, should be excluded. Cholestatic elevation os serum enzymes: The first option should be to establish the origin of the alkaline phosphatase elevation, with the evaluation of the GGT levels to confirm the hepatic origin. The next step should be to distinguish the presence of an extrahepatic (biliary obstruction) or intrahepatic (PBC, PSC, drugs, etc) cholestasis, in these cases the most important test should be the abdominal ultrasound, in order to evaluate the biliary system. Hyperbilirubinemia: Non conjugated hyperbilirubinemia (hemolysis, ineffective erythropoiesis, Gilbert or Criggler-Najjar syndromes) and conjugated hyperbilirubinemia, an unusual situation in which Rotor and Dubin-Johnson Syndromes should be considered. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases. At present, there are not prospective studies to evaluate the efficacy of the liver function tests. To carry out a complete medical history, an appropriate physical examination and the appropriate application of non-invasive diagnostic tests (serology, iron levels, autoimmunity or abdominal ultrasound) allow to perform a right diagnosis in most patients, making more complex tests, including liver biopsy, secondary.

Epstein-Barr Virus Hepatitis Masquerading as Painless Jaundice.

Epstein-Barr virus (EBV) infection typically presents with pharyngeal symptoms and subclinical transaminitis. We present a case of a 27-year-old woman with no known past medical history who presented with painless jaundice and dark-colored urine for three days. Her review of systems was negative for fever, sore throat, nausea, vomiting, pruritus, or rash. Her last sexual contact was six months ago with a male partner, and she only drank alcohol socially. Family and surgical history were non-significant. Physical examination revealed 3+ bilateral conjunctival icterus without abdominal tenderness or organomegaly. She had elevated transaminases: alanine transaminase (ALT) of 1287U/L and aspartate aminotransferase of (AST) 1057U/L but her alkaline phosphatase (ALP) was only slightly above normal at 109U/L (normal range 35-104U/L), with a direct hyperbilirubinemia - total bilirubin 9.5mg/dl, direct bilirubin 6.8mg/dl; the abdominal ultrasound revealed non-dilated bile ducts. Hepatitis A, B, and C serology was negative, but her EBV serology showed an infection. She had incidental thalassemia minor without splenomegaly or asterixis. She was managed conservatively, and her liver enzymes trended down with supportive management. Although EBV is an uncommon cause of painless jaundice, this diagnosis should be considered, especially when other more common causes of jaundice have been ruled out. A high index of suspicion should be maintained to detect EBV hepatitis as it can easily be diagnosed through serological testing.

Glycogen hepatopathy in type-1 diabetes mellitus: A case report.

It has been studied that fluctuating glucose levels may superimpose glycated hemoglobin in determining the risk for diabetes mellitus (DM) complications. While non-alcoholic steatohepatitis (NASH) remains a predominant cause of elevated transaminases in Type 2 DM due to a strong underplay of metabolic syndrome, Type 1 DM can contrastingly affect the liver in a direct, benign, and reversible manner, causing Glycogen hepatopathy (GH) - with a good prognosis. A 50-year-old female with history of poorly controlled type 1 DM, status post cholecystectomy several years ago, and obesity presented with nausea, vomiting, and abdominal pain. Her vitals at the time of admission were stable. On physical examination, she had diffuse abdominal tenderness. Her finger-stick glucose was 612 mg/dL with elevated ketones and low bicarbonate. Her labs revealed abnormal liver studies: AST 1460 U/L, ALP: 682 U/L, ALP: 569 U/L, total bilirubin: 0.3mg/dL, normal total protein, albumin, and prothrombin time/ international normalized ratio (PT/INR). A magnetic resonance cholangiopancreatography (MRCP) demonstrated mild intra and extra-hepatic biliary ductal dilation without evidence of choledocholithiasis. She subsequently underwent a diagnostic ERCP which showed a moderately dilated CBD, for which a stent was placed. Studies for viral hepatitis, Wilson's Disease, alpha-1-antitrypsin, and iron panel came back normal. Due to waxing and waning transaminases during the hospital course, a liver biopsy was eventually done, revealing slightly enlarged hepatocytes that were PAS-positive, suggestive of glycogenic hepatopathy. With treatment of hyperglycemia and ensuing strict glycemic control, her transaminases improved, and she was discharged. With a negative hepatocellular and cholestatic work-up, our patient likely had GH, a close differential for NASH but a poorly recognized entity. GH, first described in 1930 as a component of Mauriac syndrome, is believed to be due to glucose and insulin levels fluctuation. Dual echo magnetic resonance imaging sequencing and computed tomography scans of the liver are helpful to differentiate GH from NASH. Still, liver biopsy remains the gold standard for diagnosis. Biopsy predominantly shows intra-cellular glycogen deposition, with minimal or no steatosis or inflammation. As GH is reversible with good glycemic control, it should be one of the differentials in patients with brittle diabetes and elevated transaminases. GH, however, can cause a dramatic elevation in transaminases (50-1600 IU/L) alongside hepatomegaly and abdominal pain that would raise concern for acute liver injury leading to exhaustive work-up, as was in our patient above. Fluctuation in transaminases is predominantly seen during hyperglycemic episodes, and proper glycemic control is the mainstay of the treatment.

A case of brucellosis presenting with acute hepatitis and bicytopenia.

Although liver involvement is frequently seen in brucellosis, acute hepatitis is a rare clinical entity. In its progress, haematological findings are non-specific and vary in respect to severity. In this paper, we present a case of brucellosis with acute hepatitis and bicytopenia without anaemia. A 19-year-old man presented with a 2-week history of fever, sweating, low back and leg pain, lassitude, loss appetite, nausea and vomiting. He gave a history of raw milk ingestion and animal contact. Physical examination showed signs of icteric skin and sclera, tenderness in the right hypochondriac region and hepatosplenomegaly. On admission to hospital, laboratory tests showed WBC 3500/mmc (polymorphs 63% and lymphocytes 33%), haemoglobin 13.8 g/dL, platelet 89000/mmc, erythrocyte sedimentation rate 19 mm/h, and C-reactive protein 21.7 mg/dL (N<0.8 mg/dL). Biochemical tests were as follows: AST 771 U/L, ALT 471 U/L, ALP 355 U/L, GGT 432 U/L, total bilirubin 2.61 mg/dL, direct bilirubin 1.45 mg/dL and albumin 3.7 g/dL. Viral hepatitis markers were found to be negative (HBsAg, anti-HBc total, anti-HBc IgM, anti-HAV IgM, and anti-HCV). Blood culture grew Brucella melitensis. Leukopenia and thrombocytopenia returned to normal levels at the 7th and 14th day of his admission, respectively. Liver function tests improved at the 28th day. Treatment of the brucellosis was performed with antibiotics (tetracycline 500 mg orally four times daily for 6 weeks and streptomycin 1 g IM once daily for 21 days). Finally, a case of brucellosis with acute hepatitis and bicytopenia was treated with a successful outcome. In conclusion, we suggest that due consideration be taken of bicytopenia/pancytopenia and acute hepatitis in brucellosis cases in Turkey, an endemic region.

[A case with Rotor syndrome in hyperbilirubinemic family].

Rotor syndrome is a rare, benign familial disorder characterized by chronic fluctuating, nonhemolytic and predominantly conjugated hyperbilirubinemia with normal hepatic histology. In contrast to Dubin-Johnson syndrome, there is no liver pigmentation in Rotor syndrome. A 36-year-old man was admitted due to asymptomatic persistent jaundice. His siblings had jaundice with direct hyperbilirubinemia. Physical examination revealed icteric sclerae without hepatosplenomegaly. Laboratory findings showed increased serum bilirubin with direct bilirubinemia. Hepatic uptake and storage capacity of indocyanine green was markedly reduced, while excretion into bile was slightly suppressed. Markedly decreased hepatic uptake and poor visualization of the gallbladder and biliary tract were shown in 99mTc-DISIDA scan. Histology of the liver showed mild steatosis without pigmentation. We report a case with the review of literature.

[Positive diagnosis of Gilbert syndrome. Retrospective analysis of 59 cases with special reference to the nicotinic acid test].

The results of a retrospective analysis of 59 patients with Gilbert's syndrome are presented. All the patients were selected on the basis of repeatedly documented, predominantly unconjugated hyperbilirubinemia in the absence of liver or hemolytic disease. The peak incidence of Gilbert's syndrome was in the 15-30 years age group with males predominating almost fivefold. Scleral icterus or a laboratory finding of hyperbilirubinemia represented the major reasons for workup. Presenting symptoms such as fatigue, upper abdominal pain and fat intolerance were largely nonspecific. Whereas minimal values for total serum bilirubin concentrations were, at l.57 +/- 0.56 mg/dl (mean +/- S.D.), often within the normal range (less than 1.2), maximal values were always clearly elevated (2.05 +/- 0.65). The sex difference in bilirubin levels was also maintained in the Gilbert's syndrome, since mean values in women were lower than in men. As expected, neither liver scan nor histology yielded evidence of structural abnormalities. The results of liver function studies such as galactose elimination capacity, aminopyrine breath test, or fasting and postprandial serum bile acids, were all within normal limits. In contrast, the initial plasma disappearance of bromsulphthalein (BSP-k1) was reduced in 6 patients to a mean of 8.7% per min (normal value 12.6 +/- 1.6), which suggests that these subjects belong to the Gilbert type with diminished hepatic clearance of anionic dyes. The hematological investigations, including hemoglobin electrophoresis, Coombs tests and erythrocyte enzymes, yielded normal results. However, osmotic fragility was increased in 5 cases and erythrocyte survival reduced to less than 24 days in 9 cases (of 17 investigated). In 35 patients, a nicotinic acid test was performed in which total serum bilirubin rose within 3 hours from a mean of 1.66 +/- 0.7 to 3.51 +/- 0.75 mg/dl. Between the third and fifth hour bilirubin levels plateaued, yielding retention values of 98%, 92% and 92% respectively. These retention values may be considered in indirect estimate of bilirubin clearance. Retentions exceeding 70% after 5 hours correspond to bilirubin clearances of less than 20 ml/min, representing evidence in favour of the diagnosis of Gilbert's syndrome.

Hemolytic Anemia: Sneaky Cause, Leaky Valve.

Intravascular hemolysis is a known complication of prosthetic heart valves. Severe hemolysis is rare (<1%) with the use of newer generation prosthetic valves. This usually occurs due to paravalvular leaks (PVLs). We present a case of hyperbilirubinemia and hemolytic anemia occurring as a result of a PVL of a prosthetic mechanical mitral valve. The patient was a 49-year-old female with a past medical history of rheumatic heart disease status following two mitral valve replacements each with a mechanical prosthesis; she presented with a complaint of worsening fatigue, epigastric pain, nausea, and vomiting. On examination, she had scleral icterus. Heart auscultation revealed a crisp mechanical S1 click and a soft 2/6 systolic murmur in the left lower sternal border. Her abdomen was soft with mild epigastric and right upper quadrant tenderness, and no Murphy's sign. Her labs revealed a white blood cell count of 7.0 x 10<sup3</sup/microliter, hemoglobin 10.5 g/dL, hematocrit 29.7%, total bilirubin 6.9 mg/dL, direct bilirubin 0.8 mg/dL, alkaline phosphatase (ALP) 62 U/L, aspartate aminotransferase (AST) 79 U/L, and alanine aminotransferase (ALT) 56 U/L. An ultrasound of the abdomen revealed cholelithiasis without pericholecystic fluid collection and no ultrasonographic Murphy's sign. Magnetic resonance cholangiopancreatography ruled out acute cholecystitis or intra- or extra-hepatic biliary ductal dilatation. A transesophageal echocardiogram showed a well-seated mitral valve prosthesis with a significant PVL and likely moderate mitral regurgitation. The patient was evaluated for possible hemolysis. Lactate dehydrogenase was 1155 U/L, haptoglobin was <30 mg/dL, and reticulocyte count was 5.2%. She underwent a mitral valve re-replacement with a mechanical prosthesis. An echocardiogram after the surgery showed the mechanical prosthesis mitral valve with no residual PVL.

<i>Shigella sonnei</i> Bacteremia Presenting with Profound Hepatic Dysfunction.

Worldwide, Shigellosis is a significant public health issue, associated with nearly one million deaths annually. About half a million cases of <iShigella</i infection are reported annually in the United States. <iShigella</i bacteremia is uncommon and generally seen in children and immunocompromised adults. We present a case of a <iShigella sonnei</i bacteremia with marked hepatic derangement in a 27-year-old previously healthy homosexual male with history of Roux-en-Y gastric bypass, who presented to the emergency room with a 4-day history of loose watery stool, abdominal cramps, nausea and vomiting, and yellow skin of 2-day duration. He reports similar diarrhea illness in two close contacts in preceding days. On examination, he was fully oriented but dehydrated, icteric, and febrile. Laboratory data revealed WBC of 2200/<iμ</iL, elevated AST and ALT (201 IU/L, 73 IU/L resp.), normal alkaline phosphatase, elevated total and direct bilirubin of 8.2 mg/dL and 4.4 mg/dL, albumin of 3.2 g/dL, INR of 2.9, prothrombin time of 31.7, and platelet of 96,000/<iμ</iL. Workup for infectious, autoimmune and medication-induced hepatitis, Wilson's disease, and hemochromatosis was negative. Abdominal ultrasound and computed tomography of the abdomen showed hepatic steatosis and right-sided colitis. Stool and blood cultures were positive for <iShigella sonnei</i. He was treated with ciprofloxacin with improvement in liver function. Follow-up blood test 4 months later was within normal limits.

Rotor syndrome

Diagnosis Increased conjugated hyperbilirubinemia is the hallmark for diagnosing Rotor syndrome. There is no distinct black pigmentation of the liver as seen in a similar, Dubin-Johnson Syndrome. Genes, SLCO1B1 and SLCO1B3 that result in complete functional deficiencies of both protein products (OATP1B1 and OATP1B3, respectively), are also present. Rotor syndrome is largely a diagnosis of exclusion. Serological abnormalities in Rotor syndrome only include elevated total serum bilirubin (typically elevated between 2 to 5 mg/dL but may be as high as 20 mg/dL). Most of the time, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase levels are normal, but mild elevations can be seen. If any of these lab values are markedly elevated, investigation for other, more serious conditions is warranted.

Jaundice -- Evaluation

AST/ALT ratio is more than 2 to 1 in alcoholic liver disease. AST and ALT values are in 1000s; then the hepatocellular disease is likely due to toxins like acetaminophen or ischemia or viral. If ALP levels are five times elevated than normal and liver transaminases are normal or less than two times normal, then the most likely cause is biliary obstruction. The high serum ALP levels due to a biliary injury can be differentiated from bone disorders by ordering a GGT serum profile, increased levels confirm hepatic origin. If AST, ALT and ALP levels are normal- then the jaundice is not due to liver or bile duct injury. The cause must probably be pre-hepatic: inherited disorders of liver conjugation or blood disorders or defect in hepatic excretion (Rotor, Dubin-Johnson). Serum Bilirubin - whether there is a rise in unconjugated or conjugated bilirubin

Bilirubin

Very high levels of bilirubin may be caused by: Neonatal hyperbilirubinemia, where the newborn's liver is not able to properly process the bilirubin causing jaundice Unusually large bile duct obstruction, e.g. stone in common bile duct, tumour obstructing common bile duct etc. Severe liver failure with cirrhosis (e.g. primary biliary cirrhosis) Crigler–Najjar syndrome Dubin–Johnson syndrome Choledocholithiasis (chronic or acute). Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis. To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., hepatitis A, B, C, delta, E, etc.). Jaundice

Bilirubinuria

In medicine, bilirubinuria is an abnormality in which conjugated bilirubin is detected in the urine. The term "biliuria" is very similar, but more general. It refers to the presence of any bile pigment in the urine. Conjugated bilirubin is detected in urine at bilirubinemia of approximately 30-34 mmol/l or 2 mg/dL. In this concentration of conjugated bilirubin in the blood appears as yellowness of the mucous membranes and sclera. Causes The most common cause of bilirubinuria is hepatocellular disease. More rare causes include inherited disorders, such as Dubin–Johnson syndrome and Rotor syndrome. Although Gilbert's syndrome and Crigler–Najjar syndrome are characterized by increased bilirubin in the serum, the bilirubin in these inherited disorders is not conjugated and thus not excreted in the urine.

InternalMed_Harrison

Isolated elevation of the bilirubin Indirect hyperbilirubinemia (direct < 15%) See Table 58-1 Direct hyperbilirubinemia (direct > 15%) See Table 58-1 Drugs Rifampicin Probenecid Inherited disorders Dubin-Johnson syndrome Rotor syndrome 1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen and core antibody (IgM) Hepatitis C RNA 2. Toxicology screen Acetaminophen level 3. Ceruloplasmin (if patient < 40 years of age) 4. ANA, SMA, SPEP Inherited disorders Gilbert's syndrome Crigler-Najjar syndromes Hemolytic disorders Ineffective erythropoiesis Bilirubin and other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase See Table 58-2 Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST See Table 58-3 Dilated ducts Extrahepatic cholestasis CT/MRCP/ERCP Liver biopsy Liver biopsy MRCP/Liver biopsy Results negativeResults negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if

InternalMed_Harrison

FAMILIAL DEFECTS IN HEPATIC EXCRETORY FUNCTION Dubin-Johnson Syndrome (DJS) This benign, relatively rare disorder is characterized by low-grade, predominantly conjugated hyperbilirubinemia (Table 359-2). Total bilirubin concentrations are typically between 34 and 85 μmol/L (2 and 5 mg/dL) but on occasion can be in the normal range or as high as 340–430 μmol/L (20–25 mg/dL) and can fluctuate widely in any given patient. The degree of hyperbiliru-2003 binemia may be increased by intercurrent illness, oral contraceptive use, and pregnancy. Because the hyperbilirubinemia is due to a predominant rise in conjugated bilirubin, bilirubinuria is characteristically present. Aside from elevated serum bilirubin levels, other routine laboratory tests are normal. Physical examination is usually normal except for jaundice, although an occasional patient may have hepatosplenomegaly.

InternalMed_Harrison

Review drug list Hepatitis C antibody Hepatitis B surface Ag Iron, TIBC, ferritin ANA, SPEP Ceruloplasmin (if patient < 40) Ultrasound to look for fatty liver <15% Direct Gilbert’s syndrome Isolated elevation of the bilirubin Hepatocellular pattern (see Table 358-1) W/U negative W/U negative W/U negative Dilated ducts W/U positive Isolated elevation of the alkaline phosphatase Cholestatic pattern (see Table 358-1) Consider liver biopsy ERCP/Liver Bx CT/MRCP/ERCP Liver Bx Ducts not dilated Dilated ducts AMA positive AMA negative Alkaline phos. of liver origin Alkaline phos. of bone origin Bone Eval Ducts not dilated and/or AMA positive MRCP Evaluation for hemolysis Dubin-Johnson or Rotor syndrome Hemolysis Fractionate bilirubin >15% Direct Check AMA Review drugs Ultrasound Liver Tests Fractionate the alkaline phosphatase or check GGT or 5' nucleotidase to assess origin of alkaline phosphatase Ultrasound Review drug list Check AMA Liver biopsy R/O Celiac disease Consider other

[Broad beans as a cause of acute hemolytic anemia].

A previously healthy 17-year-old Greek boy suddenly developed jaundice of sclerae and skin. In addition, physical examination revealed a pale appearance. He also reported feeling tired and weak. The haemoglobin level was 9.6 g/dl, lactate dehydrogenase activity 335 U/l, bilirubin concentration 3.2 mg/dl (direct bilirubin 0.7 mg/dl, indirect bilirubin 2.5 mg/dl), haptoglobin concentration 48.8 mg/dl. As haemolytic anaemia was assumed, direct questioning elicited the fact that the patient had, for the first time in his life, eaten 300 g of broad beans (Vicia faba) on each of two days, namely 3 and 2 days before the appearance of jaundice. Absence of glucose-6-phosphate dehydrogenase activity in the red blood corpuscles confirmed the diagnosis of favism. On symptomatic treatment both the enzyme activities and the bilirubin level fell to normal within one week, and the haemoglobin level was 15.7 g/dl after 4 weeks.

Dubin–Johnson syndrome

Dubin–Johnson syndrome is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to Rotor syndrome. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed. Signs and symptoms Around 80 to 99% of people with Dubin-Johnson syndrome have jaundice, abnormal urinary color, biliary tract abnormality, and conjugated bilirubinemia. Around 30 to 79% of people with the disorder have abnormality of the gastric mucosa. Other rare symptoms include fever and fatigue.

Gilbert's syndrome

Dubin–Johnson syndrome and Rotor syndrome are rarer autosomal recessive disorders characterized by an increase of conjugated bilirubin. Viral hepatitis associated with increase of conjugated bilirubin can be excluded by negative blood samples for antigens specific to the different hepatitis viruses. Cholestasis can be excluded by normal levels of bile acids in plasma, the absence of lactate dehydrogenase, low levels of conjugated bilirubin, and ultrasound scan of the bile ducts.

InternalMed_Harrison

Laboratory Tests A battery of tests are helpful in the initial evaluation of a patient with unexplained jaundice. These include total and direct serum bilirubin measurement with fractionation; determination of serum aminotransferase, alkaline phosphatase, and albumin concentrations; and prothrombin time tests. Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular process and a cholestatic process (Table 358-1; Fig. 58-1)—a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a rise in the aminotransferases that is disproportionate to that in ALP, whereas patients with a cholestatic process have a rise in ALP that is disproportionate to that of the aminotransferases. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in

Liver function tests

The increase in predominantly unconjugated bilirubin is due to overproduction, reduced hepatic uptake of the unconjugated bilirubin and reduced conjugation of bilirubin. Overproduction can be due to the reabsorption of a haematoma and ineffective erythropoiesis leading to increased red blood cell destruction. Gilbert's syndrome and Crigler–Najjar syndrome have defects in the UDP-glucuronyl-transferase enzyme, affecting bilirubin conjugation. The degree of rise in conjugated bilirubin is directly proportional to the degree of hepatocyte injury. Viral hepatitis can also cause the rise in conjugated bilirubin. In parenchymal liver disease and incomplete extrahepatic obstruction, the rise in conjugated bilirubin is less than the complete common bile duct obstruction due to malignant causes. In Dubin–Johnson syndrome, a mutation in multiple drug-resistance protein 2 (MRP2) causes a rise in conjugated bilirubin.

Dubin-Johnson Syndrome -- History and Physical

Most patients with DJS are often young adults and are asymptomatic. Hyperbilirubinemia is found as an incidental finding while undergoing routine testing or being tested for some other unrelated problem. They may rarely present with mild icterus, weakness, and/or upper abdominal pain. Pruritus is not a symptom of DJS since serum total bile acid levels are normal. In women, the condition may be subclinical and discovered because of hyperbilirubinemia or obvious jaundice once started on oral contraceptives or becoming pregnant, at which time development of jaundice may lead to the establishment of the diagnosis. Except for mild icterus, physical examination results are within normal limits. [7] [4]

Impaired Bilirubin Conjugation -- History and Physical

Gilbert syndrome presents in patients as a mild, intermittent, and prolonged unconjugated hyperbilirubinemia without hemolysis. It also presents with normal LDH and haptoglobin  levels and reticulocyte counts in addition to normal liver function tests. Liver ultrasound is normal . In fact, Gilbert syndrome is most commonly asymptomatic, and it is often found incidentally on routine blood testing conducted for other reasons. Upon physical exam, this syndrome can manifest as jaundice. Nonspecific symptoms of abdominal cramps, fatigue, and malaise may also present with the disease. A thorough history should be taken to ascertain whether the patient is taking drugs that are metabolized through glucuronidation such as tolbutamide, rifamycin, HIV protease inhibitors, gemfibrozil, and statins, which could contribute to drug toxicity.

Jaundice

Laboratory results for liver panels are frequently compared by the magnitude of their differences, not the pure number, as well as by their ratios. The AST:ALT ratio can be a good indicator of whether the disorder is alcoholic liver damage (above 10), some other form of liver damage (above 1), or hepatitis (less than 1). Bilirubin levels greater than 10 times normal could indicate neoplastic or intrahepatic cholestasis. Levels lower than this tend to indicate hepatocellular causes. AST levels greater than 15 times normal tend to indicate acute hepatocellular damage. Less than this tend to indicate obstructive causes. ALP levels greater than 5 times normal tend to indicate obstruction, while levels greater than 10 times normal can indicate drug (toxin) induced cholestatic hepatitis or cytomegalovirus infection. Both of these conditions can also have ALT and AST greater than 20 times normal. GGT levels greater than 10 times normal typically indicate cholestasis. Levels 5–10

Severe jaundice due to coexistence of Dubin-Johnson syndrome and hereditary spherocytosis: a case report.

Dubin-Johnson syndrome is a chronic, benign, intermittent jaundice, mostly of conjugated hyperbilirubinemia. The level of bilirubin is not expected to be more than 20 mg/dl in this syndrome. In this article, we report a patient who was evaluated for hyperbilirubinemia and liver function test abnormalities and diagnosed with Dubin-Johnson syndrome coexisting with hereditary spherocytosis. We suggest that other diseases should be investigated if patients with Dubin-Johnson syndrome present with severe hyperbilirubinemia. Dubin-Johnson syndrome accompanied by hemolytic diseases might also have high coproporphyrin levels (as in Rotor's syndrome) than expected in pure Dubin-Johnson syndrome.

[A young man with acute generalised jaundice and intermittent epigastric pain].

A 24-year-old Iraqi was admitted to our hospital with acute generalised jaundice and intermittent epigastric pain. His family doctor suspected a viral hepatitis. Two days prior admission the patient had consumed large quantities of alcohol and had subsequently taken analgetic dosages of paracetamol and acetylsalicylic acid. Besides an otherwise inconspicuous physical examination the laboratory results revealed a distinct hemolysis with macrocytic, hyperchromic anaemia and negative Coombs-test. Indirect bilirubin was initially 25.2 mg/dl, LDH 2367 U/l and reticulocytes 4.4 %; haptoglobin and transferrine levels were correspondingly low. A hemoglobinopathies was excluded by hemoglobin-electrophoresis and a blood-smear. DIAGNOSIS, TREATMENT AND FURTHER COURSE: A glucose-6-phosphate dehydrogenase deficiency (G6PDD) was suspected and subsequently confirmed within three days. Acetylsalicylic acid, the most probable trigger, and other possible triggers like ciprofloxacin, metamizole, and cotrimoxazole were avoided; the jaundice faded rapidly, and the laboratory-parameters almost normalized. In patients with acute jaundice, abdominal pain, and signs of hemolysis collection of accurate anamnestic information is essential. In case of a young male with positive family-history, applicable ethnical origin, and intake of potential oxidative stressors a G6PDD should be suspected and result in requesting specific tests. Analgetic therapy with metamizole must be strictly avoided.

[Fulminate liver failure in a 39-year-old female patient with leukocytosis, unclear fever, and arthralgic pain].

Fulminate liver insufficiency can have many causes and is a challenge for differential diagnosis. A 39-year-old woman was admitted because of a nonitching macular-papular exanthema on both thighs with spreading to the trunk. In addition, the patient complained of dysphagia, symmetrical arthralgias, myalgias, fever of 38 degrees C, and night sweats. An outpatient treatment with nonsteroidal antirheumatics, antihistamines and penicillin was started for 3 days before admission. On admission, a neutrophilic leukocytosis (23.6 Gpt/l), an increase in C-reactive protein (185 mg/l), and a ferritin level of 1,740 microg/l were found. Liver enzymes were increased (alanine aminotransferase 1.03 micromol/l.s, aspartate aminotransferase 1.06 micromol/l.s, gamma-glutamyltransferase 2.73 micromol/l.s, and lactate dehydrogenase 12.48 micromol/l.s). Sonographic examination showed a mild hepatosplenomegaly, but otherwise normal findings. X-rays of the lungs, hands, and ankles were normal. An echocardiography was within normal limits. Extensive serologic investigations including assays for hepatitides A, B and C as well as repeated blood cultures were negative. Antibiotic therapy was continued without any improvement. In addition, acetaminophen (4 x 1,000 mg/day) and ibuprofen (3 x 600 mg/day) were given. Liver function worsened and an icterus developed. The patient was transferred to the authors' university hospital. Because of the clinical findings of fever episodes, a typical macular exanthema, lymphadenopathy, hepatosplenomegaly, arthralgias, myalgias, dysphagia, and the presence of neutrophilic leukocytosis, fever, an increase in ferritin, but negative serologic titers and no bacteremia, a working diagnosis of Still's disease was made. The patient was treated with high-dose methylprednisone (250 mg/day for 3 days, then 100 mg/day). Liver biopsy revealed subacute hepatitis with necrosis and accompanying cholangitis. The prednisone therapy induced a fast remission and improvement of liver function, liver transplantation was not necessary. The patient is, 16 months after the incident, without symptoms under prednisone 3 mg/day, and the liver function is normal. The etiology of Still's disease is unknown and the disease is characterized by fever episodes, a typical macular-papular exanthema, lymphadenopathy, hepatosplenomegaly, and arthralgias. A mild to moderate increase in liver enzymes is often found as part of this disease. Rarely, a fulminate liver failure has been described, particularly in the presence of co-administration of nonsteroidal antirheumatics or acetaminophen. Still's disease must be considered as part of the differential diagnosis of acute liver failure, because an early diagnosis and consequent therapy with prednisone may prevent the need for liver transplantation.

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exists. Serum bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level is almost always elevated in biliary obstruction. A rise in alkaline phosphatase often precedes clinical jaundice and may be the only abnormality in routine liver function tests. There may be a twoto tenfold elevation of serum aminotransferases, especially in association with acute obstruction. Following relief of the obstructing process, serum aminotransferase elevations usually return rapidly to normal, while the serum bilirubin level may take 1–2 weeks to return to normal. The alkaline phosphatase level usually falls slowly, lagging behind the decrease in serum bilirubin.

Dubin–Johnson syndrome

In post mortem autopsy, the liver will have a dark pink or black appearance due to pigment accumulation. Plentiful canalicular multiple drug-resistant protein causes bilirubin transfer to bile canaliculi. An isoform of this protein is localized to the apical hepatocyte membrane, allowing transport of glucuronide and glutathione conjugates back into the blood. High levels of gamma-glutamyl transferase (GGT) help in diagnosing pathologies involving biliary obstruction. Differentiation from Rotor syndrome Dubin–Johnson syndrome is similar to Rotor syndrome, but can be differentiated by:

Gilbert's syndrome

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism. Diagnosis People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range or is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dl) compared to the normal amount of < 20 μM. GS patients have a ratio of unconjugated/conjugated (indirect/direct) bilirubin commensurately higher than those without GS. The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days, and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital: the bilirubin will decrease substantially.

[Acute pancreatitis and acalculous cholecystitis associated with viral hepatitis A].

We report the case of a 14 year-old male from Lima. He is a student with a history of bronchial asthma since age 4 receives conditional salbutamol, corticosteroids used for asthma attacks (a crisis in 2010, 1 month ago) Refuses surgery or transfusions. He presented with a two weeks for abdominal pain, nausea, fever, and jaundice. Epigastric pain is colicky and radiated back to righ upper quadrant, refers in addition to nausea and fever, for ten days notice jaundice of skin and sclera. On examen he was lucid, with jaundice of skin and mucous membranes. There was no palpable lymph nodes, abdomen with bowel sounds, soft, depressible, liver span of 15cm, positive Murphy, no peritonitis. The laboratory findings showed hemoglobin 13gr, MCV 90, platelets 461.000/mm3, WBC 4320/mm, lymphocytes 1700 (39%). total bilirubin: 8.8, B Direct: 7.6, ALT (alanine aminotransferase): 3016, AST (aspartate aminotransferase): 984, alkaline phosphatase: 250, albumin: 3.34gr%, globulin: 2.8, amylase: 589 (high serum amylase), TP: 17, INR: 1.6, VHA IgM positive. 89 mg glucose, urea 19 mg%, creatinine 0.5 mg Hemoglobin 13gr, MCV 90 Platelet 461000/mm3, WBC 4320/mm, Lymphocytes 1700 (39%). The nuclear magnetic resonance showed hepatomegaly associated with thickening of gallbladder wall without stones up to 11mm inside. No bile duct dilatation, bile duct 4mm, pancreas increased prevalence of body size. Mild splenomegaly and free fluid in the space of Morrison and right flank. Abdominal ultrasound revealed a gallbladder wall thickness (11mm), without stones in his light. Pancreas to increase volume with peripancreatic fluid free perivesicular with a volume of 430 cc. Findings consistent with acute acalculous cholecystitis and acute pancreatitis. CT-scan showed enlarged pancreas with predominance of body and tail with peripancreatic edema; the gallbladder was thickening. We report this case because the extrahepatic manifestations of viral hepatitis A infection are uncommon, specially the associated with acute acalculous cholecystitis and acute pancreatitis simultaneous.