The changes described in the question statement correspond to an early precirrhotic situation. Although alcohol is the most frequent toxicant that causes this condition, it is not the exclusive cause. Diabetes mellitus causes similar hepatic alterations: fat accumulation in hepatocytes, centroacinar fibrosis, inflammatory infiltrate by polymorphonuclear neutrophils and hyaline degeneration of perinuclear mallory. Taking this into consideration, we can rule out the second question (they are intracellular fat accumulations, not glycogen) and the fourth (if diabetes also produces this situation, there is no reason to mistrust the patient). Based on the primum non nocere and not having special relevance for the treatment if it is a focal or generalized disease, it is not necessary to repeat a liver biopsy that would not expand information, discarding the first question. Fortunately for the hypothetical patient, in the initial phase these changes are reversible when the noxa disappears, so we are left with answer number 5.

The changes described in the question statement correspond to an early precirrhotic situation. Although alcohol is the most frequent toxicant that causes this condition, it is not the exclusive cause. Diabetes mellitus causes similar hepatic alterations: fat accumulation in hepatocytes, centroacinar fibrosis, inflammatory infiltrate by polymorphonuclear neutrophils and hyaline degeneration of perinuclear mallory. Taking this into consideration, we can [HIDDEN] and the fourth (if diabetes also produces this situation, there is no reason to [HIDDEN]). Based on the primum non nocere and not having special relevance for the treatment if it is a focal or generalized disease, it is not necessary to repeat a liver biopsy that would not expand information, [HIDDEN]. Fortunately for the hypothetical patient, in the initial phase these changes are reversible when the noxa disappears, so we are left with [HIDDEN].

A 56-year-old man, diabetic and moderately overweight, presents a discrete hepatomegaly. The patient indicates that he is not a regular drinker, only exceptionally does he drink some wine. A liver biopsy shows accumulations of clear cytoplasmic vacuoles in 50% of the hepatocytes. Multiple inflammatory foci with neutrophils, Mallory's hyaline degeneration and fibrosis around the terminal hepatic venules. Point out the correct answer in this case:

Biopsy should be repeated to see if the changes are diffuse.

Diagnosis is hepatic glycogenosis associated with diabetes.

Histological changes are irreversible and will eventually lead to cirrhosis.

The injury is clearly caused by alcohol despite the patient's refusal.

It is important to reduce weight and adequately control diabetes to avoid the possible development of cirrhosis.

Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus.

Reported are the clinical and pathologic features of glycogenic hepatopathy, a pathologic overloading of hepatocytes with glycogen that is associated with poorly controlled diabetes mellitus. Fourteen cases were studied by stains, including hematoxylin and eosin, trichrome, periodic acid-Schiff, and periodic acid-Schiff with diastase. Ultrastructural analysis was performed in 2 cases. Medical records were reviewed for clinical presentations, laboratory findings, and clinical outcomes. The individuals ranged from 8 to 25 years of age. All had type I diabetes mellitus with poor glycemic control. The clinical presentations included hepatomegaly, abdominal pain, and elevated transaminases (range, 50-1600 IU/L). The transaminases were dramatically elevated in 3 cases to greater than 10 times the upper limit of normal. All biopsies showed diffusely pale staining hepatocytes on hematoxylin and eosin stains, with excessive glycogen accumulation demonstrated by periodic acid-Schiff stains. Ultrastructural examination revealed marked glycogen accumulation in the cytoplasm and nuclei. Most cases showed no evidence for fatty liver disease: steatosis was absent in 12 of 14 cases, simple steatosis was seen in 1 of 14 cases, and mild steatohepatitis was present in 1 of 14 cases. Mallory hyaline was absent in all cases, acidophil bodies were only rarely seen, and inflammation was absent or minimally present. Fibrosis was typically absent, with only 2 cases demonstrating focal mild fibrosis. Three patients had adequate follow-up and demonstrated improvement of liver enzyme levels with control of blood glucose. We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus. The pathology is distinct from steatohepatitis.

Nonalcoholic steatohepatitis.

To determine the clinical relevance of nonalcoholic steatohepatitis (NASH) and to review the available literature on the epidemiology, clinical features, histology, pathogenesis, clinical course, and management of this condition. Pertinent articles in English identified through a MEDLINE search (1966 to the present) and the bibliographies of relevant articles. All studies, including case reports, evaluating the salient features and clinical profile of NASH. Data were selected from all articles that fit the study selection criteria. Nonalcoholic steatohepatitis is a distinct clinical entity characterized by elevated plasma liver enzyme levels and liver biopsy findings that are identical to those seen in alcoholic hepatitis; patients with NASH, however, do not consume alcohol in quantities known to cause liver injury. Patients with NASH are typically obese, middle-aged women with asymptomatic hepatomegaly who are diabetic or hyperlipidemic and present with an unrelated medical problem. Analysis of liver biopsy specimens is the cornerstone of diagnosis; hepatic morphologic findings range from mild fatty degeneration and inflammation to cell degeneration, fibrosis, and cirrhosis with or without the presence of Mallory hyaline bodies. Elevated levels of free fatty acids in the liver are thought to be responsible for the development of steatohepatitis. Although NASH is most often a benign disease with an indolent course, patients with this condition occasionally develop cirrhosis, portal hypertension, and hepatic failure. In some cases, NASH may be reversed with weight reduction. Nonalcoholic steatohepatitis is an important differential diagnosis for asymptomatic patients with chronically elevated plasma liver enzyme levels, especially if obesity, diabetes, or hyperlipidemia are present. Analysis of liver biopsy specimens is necessary for diagnosis and must be done in all patients with unexplained abnormal liver function and negative results on a noninvasive workup. Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies.

Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes.

In adults with diabetes mellitus, hepatomegaly and abnormalities of liver enzymes occur as a consequence of hepatocellular glycogen accumulation, as has been well described in children. During periods of hyperglycemia glucose freely enters the hepatocytes driving glycogen synthesis, which is augmented further by administration of insulin to supraphysiologic levels. The accumulation of excessive amounts of glycogen in the hepatocytes is a function of intermittent episodes of hyperglycemia and hypoglycemia and the use of excessive insulin. Hepatic glycogenosis occurs in patients with poorly controlled insulin-dependent type I or type II diabetes. The clinical manifestations of this phenomenon may include abdominal pain and obstructive symptoms such as early satiety, nausea, and vomiting. Ascites has rarely been reported. The typical biochemical findings are mildly to moderately elevated aminotransferases, with or without mild elevations of alkaline phosphatase. Liver synthetic function is usually normal. All these abnormalities, including the hepatomegaly, are readily reversible with sustained euglycemic control. The other major cause of hepatomegaly in patients with diabetes is steatosis. This is a function of the body habitus and state of insulin resistance rather than glycemic control. However, the distinction between steatosis and glycogenosis is important: whereas steatosis may progress to fibrosis and cirrhosis, glycogenosis does not, but reflects the need for better diabetic control. Glycogenosis and steatosis cannot be distinguished reliably on ultrasound examination. The histology, however, is definitive. In glycogenosis, as in primary glycogen storage diseases, there is excess glycogen in the cytoplasm, and often also in the nucleus, of hepatocytes. The hepatocytes throughout the lobule appear pale and swollen with clearly defined cell boundaries. Ultrastructural examination reveals cytoplasmic glycogen in clumps displacing organelles to the periphery of the cell, and there is little if any steatosis. We have shown that hepatomegaly due to glycogenosis in adults with diabetes is similar in all respects to the condition seen in children. As in children, liver enzyme abnormalities are unreliable in predicting the presence or the extent of glycogenosis. Hepatic glycogenosis can occur at any age, and therefore should be included in the differential diagnosis of hepatomegaly in all insulin-requiring diabetics.

The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.

Forty-two patients with nonalcoholic steatohepatitis were followed for a median of 4.5 yr (range = 1.5 to 21.5 yr). Except for two patients with lipodystrophy, all were obese; 35 of 42 were women, 26 of 32 were hyperlipidemic and 15 were hyperglycemic. Upper abdominal pain was the most common reason for presentation. Initial liver biopsy specimens showed the presence of macrovesicular fatty infiltration, lobular (acinar) inflammation, apoptosis, Mallory bodies (in four cases) and fibrosis (in 18 cases). Cirrhosis was present at initial diagnosis in one subject and in another two subjects liver biopsy showed marked fibrosis with disturbed architecture. Serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. However, one patient showed progression from fibrosis to cirrhosis during the 5-yr observation period, and in the patients with extensive fibrosis the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation. The patient with cirrhosis later died of hepatocellular carcinoma. The severity or type of hepatic change did not correlate with the degree of obesity, hyperlipidemia or hyperglycemia. However, in individual patients, poorly controlled diabetes and rapid weight loss preceded the onset of steatohepatitis. We conclude that nonalcoholic steatohepatitis is a cause of hepatic inflammation histologically resembling that of alcohol-induced liver disease but usually slowly progressive and of low-grade severity. However, the disorder may ultimately result in cirrhosis. Nonalcoholic steatohepatitis should be distinguished from alcoholic steatohepatitis and recognized as a further cause of "cryptogenic cirrhosis."

Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus.

Five patients with maturity-onset diabetes mellitus and hepatomegaly were studied. This group in cluded moderately obese females in whom hepatomegaly and abnormal liver studies were associated with a marked elevation in the erythrocyte sedimentation rate. Liver biopsies from all 5 showed fatty steatosis and pericentral fibrosis. In 3 of the 5, fibrous bridging between central veins and portal tracts was present. Collagen surrounded swollen hepatocytes, some of which contained intracellular hyalin indistinguishable from Mallory's hyalin. Polymorphonuclear neutrophils and regenerating nodules were not present. None of the patients had a history of alcohol use, and in 2 followed closely for 2 yr, alcohol was never detected in random blood samples. The recognition of this morphologic lesion may help to clarify the significance of this finding as an intermediate lesion between fatty steatosis and cirrhosis in diabetics.

Hepatocellular carcinoma with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) was originally believed to be a benign disease. However, it has been recently revealed that NASH could lead to irreversible liver disease in some patients. We report an unusual case of hepatocellular carcinoma (HCC) in a 76-year-old man with NASH. He had no history of alcohol consumption, drug use, or blood transfusion. He was negative for all serological viral markers and autoantibodies. In addition, he was obese (body mass index [BMI], 30.75 kg/m(2)) and had type 2 diabetes mellitus. A liver biopsy specimen showed moderate steatosis with necroinflammatory changes, ballooning degeneration, Mallory bodies, pericellular fibrosis, and evidence of nodular regeneration. He was diagnosed with NASH with cirrhosis. Simultaneously, a liver tumor, measuring 19 mm in diameter, was detected in segment 6. A tumor biopsy specimen revealed well-differentiated HCC, and imaging modalities confirmed the characteristics of HCC. To our knowledge, ten patients who had HCC with NASH were reported. In all patients with NASH and HCC, cirrhosis was present. Patients with NASH and cirrhosis may progress to HCC, and regular screening, based on tumor markers and imaging modalities, is needed to detect HCC in patients with NASH and cirrhosis.

Nonalcoholic steatohepatitis and cirrhosis with Mallory's hyalin with ultrastructural study of one case.

Clinical features and liver biopsy findings were studied in six patients with nonalcoholic steatohepatitis associated with hyalin. A comparative study was made on the ultrastructure of the hyalin in one patient with nonalcoholic steatohepatitis and in one patient with alcoholic hepatitis. The patients, all over 50 years old, comprised two females and one male with steatohepatitis and three females with micronodular cirrhosis. They showed obesity, hepatomegaly, and mild abnormalities on laboratory tests. Three of them showed maturity-onset diabetes. The hyalin was found in the cytoplasm of swollen hepatocytes of the centrilobular or in the peripheral region of nodules and was accompanied by necrosis. Ultrastructurally, the hyalin comprised filamentous structures and vesicular or angular structures resembling disorganized circular or branched rough endoplasmic reticulum. It resembled that found in the liver of patients with alcoholic hepatitis.

Hepatic Glycogenosis: An Underdiagnosed Entity?

Hepatic glycogenosis (HG) is a rare complication of long-standing poorly controlled type 1 diabetes mellitus (T1DM), which is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD). Despite the existence of several reports in the literature, it still is underrecognized, even among gastroenterologists. Differential diagnosis between these entities is essential since they have different prognoses. We report a case of an 18-year-old female, with a medical history of poorly controlled T1DM, admitted to an intensive care unit with severe diabetic ketoacidosis (DKA). Upon admission, aminotransferases were significantly elevated; bilirubin and coagulation tests were normal. Despite adequate DKA treatment, she had persistently elevated aminotransferases and hyperlactacidemia. Imaging studies showed hepatomegaly and bright liver parenchyma. Extensive laboratory workup was negative for other causes of liver disease. So, a liver biopsy was performed, which was consistent with the diagnosis of HG. Under strict metabolic control, she had progressive improvement, achieving biochemical normalization within 6 months. This case highlights the need for clinicians to be aware of this condition due to non-negligible differences between HG and NAFLD, with the latter progressing to fibrosis, and ultimately cirrhosis and hepatocarcinoma. On the opposite, HG is considered a benign condition, associated with an excellent prognosis that can be reversible after adequate metabolic control. Liver biopsy remains the gold standard method for HG diagnosis since it can distinguish it from NAFLD.

Hepatic glycogenosis: An underdiagnosed complication of diabetes mellitus?

Hepatic glycogenosis (HG) is characterized by excessive glycogen accumulation in hepatocytes and represents a hepatic complication of diabetes that particularly occurs in patients with longstanding poorly controlled type 1 diabetes (T1D). HG has been reported to be a very rare disease, although it is believed to be extremely underdiagnosed because it is not possible to distinguish it from non-alcoholic fatty liver disease (NAFLD) unless a liver biopsy is performed. In contrast to HG, NAFLD is characterized by liver fat accumulation and is the more likely diagnosis for patients with type 2 diabetes and metabolic syndrome. The pathogenesis of HG involves the concomitant presence of insulin and excess glucose, which increases glycogen storage in the liver. HG is characterized by a transient elevation in liver transaminases and hepatomegaly. Differentiating between these two conditions is of the utmost importance because HG is a benign disease that is potentially reversible by improving glycemic control, whereas NAFLD can progress to cirrhosis. Therefore, HG should be suspected when liver dysfunction occurs in patients with poorly controlled T1D. The aim of this article is to review the epidemiology, clinical characteristics, pathogenesis and histology of HG.

Alcoholic liver disease

urinary loss. The magnitude of leukocytosis (white blood cell depletion) reflects severity of liver injury. Histologic features include Mallory bodies, giant mitochondria, hepatocyte necrosis, and neutrophil infiltration in the area around the veins. Mallory bodies, which are also present in other liver diseases, are condensations of cytokeratin components in the hepatocyte cytoplasm and do not contribute to liver injury. Up to 70% of patients with moderate to severe alcoholic hepatitis already have cirrhosis identifiable on biopsy examination at the time of diagnosis.

Chronic hepatitis with fatty change.

Ten patients with clinical features of chronic hepatitis showed on liver biopsy histologic evidence of chronic hepatitis plus predominantly moderate to severe fatty change. No patient had a history of excess alcohol intake, or prolonged intake of hepatotoxic drugs and steroids, and were not obese or malnourished. These cases differ from the reported cases of non-alcoholic steatohepatitis resembling alcoholic hepatitis as they occurred in relatively young health adults, predominantly males, who were not diabetic or obese. Mallory's hyalin in liver was absent in all cases. Ingestion of toxic substances was possible but no history was obtained to account for it. While these could be unusual cases of chronic non-A, non-B hepatitis, this can be only speculation until a serologic test for non-A, non-B hepatitis becomes available. Follow-up of eight patients for 1-3 years with liver biopsy showed that they had a relatively benign course with no evidence of progression to cirrhosis.

[Morphological study on 40 cases of alcoholic liver disease].

Morphological changes in liver biopsies from 40 alcoholic patients were studied, 20 of which being ordinary alcoholics (40-80g ethanol/day) and the other 20 being heavy drinkers (above 80g ethanol/day for over 20 years). All being male who have neither type B nor type C hepatitis. The basic morphological changes observed being: 1. Liver cell degeneration including fatty degeneration & focal ballooning, decrease in liver cell size, occasional giant mitochondrion and Mallory's body formation. 2. Focal necrosis with neutrophil infiltration. 3. Pericellular fibrosis of liver cells, hepatic fibrosis and early cirrhosis. Alcoholic liver disease can be divided into 5 types: I. alcoholic fatty liver (AFL), II. alcoholic hepatitis (AH), III. alcoholic hepatic fibrosis (AHF), IV. alcoholic liver cirrhosis (ALC), V. slight alcoholic liver disease (SALD). The degree of liver damage (liver cell necrosis and hepatic fibrosis) is closely related to the amount of daily ethanol intake. The progression of liver damage observed in our study is much milder than reports from Europe, the U.S. and Japan.

[Non-alcoholic fatty liver disease in obese persons with diabetes].

Obesity, diabetes and different lipid metabolic disorders are the most frequent risk factors for nonalcoholic fatty liver disease, presented with a high variability in clinical and histological findings. We presented a case of 37-year-old male, suffering from type 2 diabetes mellitus, grade III obesity (BMI 45 kg/m2) and multiple metabolic disorders. Abdominal ultrasound revealed hepatomegaly during the last six months. Laboratory diagnostics showed increased serum transaminase levels. Serologic markers for viral hepatitis B and C were negative. The patient denied significant alcohol consumption. Liver biopsy and pathohistologic finding revealed macro- (III grade) and microvesicular (I grade) fatty degeneration, as well as mixed-cell portal infiltration with moderate liver fibrosis, corresponding to the typical presentation of NASH (Non Alcoholic Steatohepatitis). NASH treatment options include the reduction of body mass and an adequate antidiabetic and dislipidemia treatment. The aim of all therapeutic measures was to stop the progression of the disease, to prevent the progression of fibrosis and the development of cirrhosis.

The pathology of diabetic hepatitis.

Liver biopsies from nine patients with maturity-onset diabetes and fatty liver hepatitis were semiquantitatively assessed, and the findings compared with those in alcoholic hepatitis. Overall appearances were similar, but the lesion in some diabetics was periportal rather than perivenular in location, and nuclear vacuolation of hepatocyte nuclei was always present. The inflammatory infiltrate often included neutrophil leucocytes, as in the alcoholic. In three patients with multiple biopsies, progression appeared to be slow, but one patient developed cirrhosis.

[Non-alcoholic fatty liver].

Non alcoholic fatty liver disease (NAFLD) and its more agressive form, non alcoholic steatohepatitis (NASH) are entities that are becoming subject of interest of the medical community in general, especially because of the increased prevalence of diabetes and obesity in the world population. There is solid evidence linking NAFLD with the so called metabolic syndrome or syndrome X, to the point of accepting hepatic steatosis and its spectrum as one more element of the latter, along with diabetes, hipertension, hypertriglyceridemia and obesity. Insulin resistance seems to be the common link between these entities. Clinical evaluation of every patient with abnormal aminotransferase levels should take into account non alcoholic fatty liver and its spectrum, especially if the subject is obese or diabetic. Despite the important developments in the field of imaging, currenty the only way to differentiate NASH from simple NAFLD is by performing a liver biopsy, which should be discussed extensively with the patient. The prognosis of simple NAFLD is generally benign, but if there is fibrosis, ballooning of the hepatocytes, inflammation and Mallory bodies there is risk to progression to cirrhosis. Liver histology in NAFLD is indistinguishable from alcoholic hepatitis, although the clinical course is generally more benign. Despite this long and protracted clinical course, an important number of subjects have complications of cirrhosis including hepatocellular carcinoma, and many patients require a liver transplantation. There is no specific treatment for this condition, although every therapeutic regimen should include a gradual and supervised weight reduction, a balanced diet and exercise, as well as correction of precipitant factors. There is currently no specific pharmacologic treatment for NASH or NAFLD. Current body of evidence and some pilot studies suggest that the future might be concentrated in agents improving insulin resistance. Meanwhile, we should do our best to study the prevalence of NAFLD in our country and, when clinically pertinent, study histologically those patients with high risk of fibrosis.

Alcoholic liver disease

In the early stages, patients with ALD exhibit subtle and often no abnormal physical findings. It is usually not until development of advanced liver disease that stigmata of chronic liver disease become apparent. Early ALD is usually discovered during routine health examinations when liver enzyme levels are found to be elevated. These usually reflect alcoholic hepatic steatosis. Microvesicular and macrovesicular steatosis with inflammation are seen in liver biopsy specimens. These histologic features of ALD are indistinguishable from those of nonalcoholic fatty liver disease. Steatosis usually resolves after discontinuation of alcohol use. Continuation of alcohol use will result in a higher risk of progression of liver disease and cirrhosis. In patients with acute alcoholic hepatitis, clinical manifestations include fever, jaundice, hepatomegaly, and possible hepatic decompensation with hepatic encephalopathy, variceal bleeding, and ascites accumulation. Tender hepatomegaly may be

Alcoholic foamy degeneration--a pattern of acute alcoholic injury of the liver.

A newly recognized clinical and morphologic pattern of acute alcoholic liver disease is described. Twenty-one patients, having the hepatic morphologic features of alcoholic foamy degeneration, were retrospectively analyzed. All patients had a significant history of chronic alcoholism. Jaundice and hepatomegaly were usually present. Hepatic encephalopathy, ascites, bleeding esophageal varices, or functional renal failure occurred in less than 10%. Usually this was the first episode of decompensation. Laboratory studies revealed a pattern of very transiently marked elevation of serum aminotransferase and more prolonged elevation of alkaline phosphatase activity and bilirubin levels. In the majority of cases, leukocytosis was absent, and serum cholesterol was elevated. The laboratory profile differed significantly from that of acute sclerosing hyaline necrosis. Serologic markers of acute viral hepatitis A and B were absent. Needle biopsy specimens of the liver revealed intact lobular architecture except for 1 case of cirrhosis. The perivenular hepatocytes revealed foamy fatty change characterized by striking cell swelling with massive accumulation of microvesicular fat, bile pigment deposition in the cytoplasm, and no displacement of the nucleus to the periphery of the cell. Megamitochondria were frequently identified. Multiple foci of hepatocyte dropout without significant parenchymal neutrophilic exudation and delicate intrasinusoidal collagen fibers were present in the perivenular area. Macrovesicular fatty change coexisted to a variable degree. The affected hepatocytes had extensive disorganization of the organelles by electron microscopy and decreased or absent functional activity by enzyme histochemical staining. These changes appear to be a purely degenerative process without inflammatory reaction. All patients in the present series showed a rapid recovery upon abstaining from alcohol.

Alcoholic hepatitis

Pathophysiology Some signs and pathological changes in liver histology include: Mallory's hyaline body – a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic. Ballooning degeneration – hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis. Inflammation – neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. These cells are particularly attracted to hepatocytes with Mallory bodies.

Hepatic arteriolosclerosis: a small-vessel complication of diabetes and hypertension.

Liver involvement in diabetes is well recognized in the form of steatohepatitis and glycogenic hepatopathy. More recently, sinusoidal fibrosis, even in the absence of steatosis, has also been suggested to be associated with diabetes (diabetic hepatosclerosis); however, case-control studies are lacking. In addition, microangiopathy (hyaline arteriolosclerosis), a well-known complication of diabetes, has not been well studied in liver. Therefore, we undertook a cross-sectional blinded study with the specific aim of evaluating the association between hepatic sinusoidal fibrosis and hepatic arteriolosclerosis (HA) with diabetes. Liver biopsy findings from 89 diabetic patients obtained between January 2006 and December 2009 were compared with those of 89 nondiabetic patients matched by age and hepatitis C virus infection status. Patients with cirrhosis, liver mass, right heart failure, significant alcohol use, or insufficient available clinical information were excluded. Medical records were reviewed for the presence of diabetes, body mass index, diabetes treatment, and comorbidities at the time of biopsy (eg, underlying liver disease, hypertension, dyslipidemia). Liver biopsies were evaluated blinded to all clinical data (including presence or absence of diabetes) for a variety of histologic features, especially patterns of fibrosis and HA. Diabetic patients had a higher average body mass index (33 vs. 30 m/kg, P=0.0039), prevalence of hypertension (78% vs. 33%, P<0.0001), and dyslipidemia (52% vs. 20%, P<0.0001). Among diabetic patients, 87% had type 2 diabetes, and 57% used insulin. Whereas sinusoidal fibrosis, with or without steatosis, was not significantly associated with the presence of diabetes, HA was significantly more prevalent among diabetic patients compared with controls: 45% versus 29% (P=0.0298). The presence of both diabetes and hypertension had a significant odds for HA: with an adjusted odds ratio of 2.632 (95% confidence interval, 1.178-5.878; P=0.0183). Biliary changes were associated with HA in some cases (10.6%).In this study, we describe the histopathologic entity of HA for the first time. It is a small-vessel complication (microangiopathy) of the liver observed mainly in patients with diabetes who also have arterial hypertension. The clinical and prognostic implications of this finding, particularly regarding liver injury, remain to be further investigated.

Fatty liver disease

Liver disease with extensive inflammation and a high degree of steatosis often progresses to more severe forms of the disease. Hepatocyte ballooning and necrosis of varying degrees are often present at this stage. Liver cell death and inflammatory responses lead to the activation of hepatic stellate cells, which play a pivotal role in hepatic fibrosis. The extent of fibrosis varies widely. Perisinusoidal fibrosis is most common, especially in adults, and predominates in zone 3 around the terminal hepatic veins. The progression to cirrhosis may be influenced by the amount of fat and degree of steatohepatitis and by a variety of other sensitizing factors. In alcoholic FLD, the transition to cirrhosis related to continued alcohol consumption is well-documented, but the process involved in non-alcoholic FLD is less clear. Diagnosis

Nonalcoholic steatohepatitis. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients.

This study reports a clinicopathological analysis of 105 patients whose liver histology showed a pattern of alcohol-like steatohepatitis. There were 32 nonalcoholic, 21 asymptomatic ambulatory, and 52 hospitalized alcoholic hepatitis patients. Female sex, obesity, and diabetes predominated in nonalcoholics. Clinical and laboratory presentation were similar in nonalcoholics and ambulatory alcoholics, but different from the hospitalized alcoholics. Histology showed an increasing degree of severity of hepatocellular damage, Mallory bodies, neutrophil and mononuclear infiltration, and pericellular and portal fibrosis from the nonalcoholics to the hospitalized alcoholics, with ambulatory alcoholics displaying an intermediate degree of severity. Steatosis and glycogenated nuclei were prevalent in the obese, diabetic nonalcoholics, of whom 47% had significant fibrosis and 8% cirrhosis, the latter present in 38% and 89% of ambulatory and hospitalized alcoholic hepatitis (P = 0.0001), respectively. In asymptomatic subjects with suspected liver disease, a liver biopsy is the only way of establishing the type and severity of liver lesions.

Hepatitis

response. Over time, this abnormal lipid deposition triggers the immune system via toll-like receptor 4 (TLR4) resulting in the production of inflammatory cytokines such as TNF that cause liver cell injury and death. These events mark the transition to steatohepatitis and in the setting of chronic injury, fibrosis eventually develops setting up events that lead to cirrhosis and hepatocellular carcinoma. Microscopically, changes that can be seen include steatosis with large and swollen hepatocytes (ballooning), evidence of cellular injury and cell death (apoptosis, necrosis), evidence of inflammation in particular in zone 3 of the liver, variable degrees of fibrosis and Mallory bodies.

Cirrhosis

In non-alcoholic fatty liver disease (NAFLD), fat builds up in the liver and eventually causes scar tissue. This type of disorder appears to be associated with obesity (40% of NAFLD cases), diabetes, protein malnutrition, coronary artery disease, and treatment with steroids. Though similar in signs to alcoholic liver disease, no history of notable alcohol use is found. Blood tests and medical imaging are used to diagnose NAFLD and NASH, and sometimes a liver biopsy is needed. Chronic hepatitis C, infection with the hepatitis C virus, causes inflammation of the liver and a variable grade of damage to the organ. Over several decades, this inflammation and damage can lead to cirrhosis. Among patients with chronic hepatitis C, 20–30% develop cirrhosis. Cirrhosis caused by hepatitis C and alcoholic liver disease are the most common reasons for liver transplant.

Glycogen Hepatopathy: A Reversible yet Relapsing Cause of Hepatitis in Type 1 Diabetics.

Glycogen hepatopathy (GH), a rare glycogen storage disease caused by genetic or acquired overactivation of hepatic glycogen synthesis enzymes, can mimic non-alcoholic fatty liver disease (NAFLD). We describe a case of biopsy-proven GH in an adult with type 1 diabetes mellitus (DM). A 33-year-old Honduran woman with a 25-year history of type 1 DM complicated by gastroparesis, multiple episodes of diabetic ketoacidosis (DKA) and hypoglycemia, and recurrent pancreatitis was referred for abnormal liver enzymes. Family history was negative for liver disease. There was no history of alcohol or recreational drug use. Patients' medications included insulin and thyroxine. Physical exam showed hepatomegaly but no stigmata of chronic liver disease. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) had ranged from 100's to over 7000 U/L while alkaline phosphatase (ALP) was elevated to over 400 IU/L. Albumin, total bilirubin, platelets, international normalized ratio (INR), eosinophils, viral hepatitis panel, antinuclear antibody (ANA), smooth muscle antibody (Ab), anti-liver-kidney microsomal (LKM) Ab, celiac serologies, ceruloplasmin, alpha 1 antitrypsin, iron studies, and acetaminophen levels were all normal. An abdominal ultrasound showed "fatty liver" and an atrophic pancreas. CT abdomen showed hepatomegaly. The common bile duct (CBD) was found to be normal on endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP). A liver biopsy was pursued eventually, demonstrating glycogenotic hepatocytes. GH is frequently misdiagnosed as NAFLD, a more common liver disease that occurs in association with diabetes While GH is known to be reversible, NAFLD has been known to progress to advanced liver disease, ranging from cirrhosis to hepatocellular carcinoma. Definite diagnosis often requires liver biopsy because of overlapping clinical and radiographical pictures. Elevation of both glucose and insulin levels in the setting of fragile DM control is thought to play a role via overstimulation of glycogen synthesis. Recommended treatment is stable "tight" glycemic control; pancreatic transplantation has resulted in sustained GH remission in two case reports. The required degree of stability and tightness of glucose control is not yet known. An increased awareness of GH is needed in an attempt to prevent delay in diagnosis, in a condition with an otherwise unknown incidence.

Alcoholic hepatitis

Alcoholic hepatitis is distinct from cirrhosis caused by long-term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Some alcoholics develop acute hepatitis as an inflammatory reaction to the cells affected by fatty change. This is not directly related to the dose of alcohol. Some people seem more prone to this reaction than others. This inflammatory reaction to the fatty change is called alcoholic steatohepatitis and the inflammation probably predisposes to liver fibrosis by activating hepatic stellate cells to produce collagen.

Clinical and pathological features of non-alcoholic steatohepatitis.

Clinical and pathological features were reviewed in 76 Japanese patients with non-alcoholic steatohepatitis (NASH). Forty-one were male and 35 were female with the mean age of 49.7 years old (range 15-75 years old, males; 46.3, females; 53.7 years old). Fifty-four percent of patients were preobese with a body mass index (BMI) between 25 and 30, while 16% of the patients were non-obese, and only 30% of the cases were morbidly obese, indicating that Japanese have a greater tendency to develop insulin-resistance and fatty liver disease than Western people. Hyperlipidemia was found in 51%, diabetes mellitus in 38%, and hypertension in 33% of the patients. Abnormally elevated liver function tests were found in one-third to two-thirds of the patients and were characteristically mild with 2- to 3-fold elevation from the normal range in the majority of the cases. Histological features of the liver were similar or identical to those reported in English literature and were characterized by fatty change, perivenular and pericellular fibrosis in zone 3, hepatocyte ballooning and necrosis with occasional Mallory's body formation and polymorphonuclear leukocyte infiltration. Mallory's bodies were found in 39% of patients and were characteristically small and poorly formed compared with those in alcoholic hepatitis. Eosinophilic granular or dirty foggy aggregated, not sufficient to be identified as Mallory's bodies, were a rather characteristic cytoplasmic expression in NASH patients. Portal inflammation and fibrosis were not found in the early stage of NASH, but were found as the disease progresses with formation of C-C and/or P-C bridging fibrosis, and eventually resulting in liver cirrhosis.

Hepatitis

Of note, liver biopsy shows identical findings in patients with ASH and NASH, specifically, the presence of polymorphonuclear infiltration, hepatocyte necrosis and apoptosis in the form of ballooning degeneration, Mallory bodies, and fibrosis around veins and sinuses. Screening for viral hepatitis The purpose of screening for viral hepatitis is to identify people infected with the disease as early as possible, even before symptoms and transaminase elevations may be present. This allows for early treatment, which can both prevent disease progression and decrease the likelihood of transmission to others.

Cirrhosis

Cirrhosis is most commonly caused by alcoholic liver disease, non-alcoholic steatohepatitis (NASH) – (the progressive form of non-alcoholic fatty liver disease), chronic hepatitis B, and chronic hepatitis C. Heavy drinking over a number of years can cause alcoholic liver disease. NASH has a number of causes, including obesity, high blood pressure, abnormal levels of cholesterol, type 2 diabetes, and metabolic syndrome. Less common causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis that disrupts bile duct function, genetic disorders such as Wilson's disease and hereditary hemochromatosis, and chronic heart failure with liver congestion. Diagnosis is based on blood tests, medical imaging, and liver biopsy.

Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose.

We present a case of rapid onset of glycogen storage hepatomegaly, caused by a massive dose of long-acting insulin and large doses of glucose, in a type-2 diabetic patient. A 41-year-old man was admitted to our hospital because of hypoglycemia and unconsciousness following subcutaneous administration of 180 units of insulin glargine in a suicide attempt. Despite continuous hypercaloric infusion with additional intravenous glucose injections, hypoglycemia persisted for 36 hours. Although the hepatic function was normal and no hepatomegaly was detected on admission, the liver function tests became abnormal and hepatomegaly was detected on hospitalization day 3. Plain abdominal computed tomography (CT) scanning confirmed liver enlargement, with hepatic CT attenuation markedly elevated at 83.7 HU. Liver biopsy revealed hepatocytic glycogen deposition with edematous degeneration. Based on these findings, the diagnosis was made as rapid onset glycogen storage hepatomegaly caused by administration of a massive dose of long-acting insulin and supplementation with large doses of glucose. With improved glycemic control, the liver function improved, the CT findings of hepatomegaly improved, and the hepatic CT attenuation decreased. Repeat liver biopsy also confirmed almost complete disappearance of glycogen deposits. When hepatic dysfunction or hepatomegaly is detected during treatment with insulin, the possibility of hepatic glycogen deposition should be considered. CT scanning and liver biopsy were useful in diagnosing this case.

Nonalcoholic steatohepatitis: a study of 49 patients.

Nonalcoholic steatohepatitis (NASH) refers to an alcoholic hepatitis-like histologic pattern found in nonalcoholic patients. A review of 543 liver biopsies diagnosed as alcoholic hepatitis yielded 49 cases of NASH. The patients were commonly middle-aged women who were obese and often diabetic. NASH was usually discovered because of abnormal liver function tests or hepatomegaly noted during evaluation of other medical problems. Histologic examination revealed the same spectrum of changes found in alcoholic hepatitis, including cirrhosis in eight patients. Follow-up information was available for 39 patients after an average length of 3.8 years. Only one patient developed hepatic decompensation or died with liver failure or portal hypertension. Repeat histologic material was available for 13 patients after a mean 3.5 years of follow-up. Five patients showed progression of fibrosis, with cirrhosis developing in two, but the other eight patients demonstrated little morphologic change. These findings indicate that NASH is, in general, a clinically mild and biologically low-grade condition, but with the potential to progress and evolve into cirrhosis in some patients. The factors promoting progression are unclear.

Pathoma_Husain

B. Fatty liver is the accumulation of fat in hepatocytes (Fig. 11.9A). 1. Results in a heavy, greasy liver; resolves with abstinence (Fig. 11.9B) C. Alcoholic hepatitis results from chemical injury to hepatocytes; generally seen with binge drinking 1. Acetaldehyde (metabolite of alcohol) mediates damage. 2. Characterized by swelling of hepatocytes with formation of Mallory bodies (damaged cytokeratin filaments, Fig. 11.10), necrosis, and acute inflammation 3. Presents with painful hepatomegaly and elevated liver enzymes (AST > ALT); may result in death D. Cirrhosis is a complication of long-term, chronic alcohol-induced liver damage; occurs in 10-20% of alcoholics V. A. Fatty change, hepatitis, and/or cirrhosis that develop without exposure to alcohol (or other known insult) B. Associated with obesity C. Diagnosis of exclusion; ALT > AST VI. HEMOCHROMATOSIS

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.

Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy.