Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
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The classic clinical presentation for type IV glycogen storage disease (branching enzyme deficiency, GSD IV) is hepatosplenomegaly with failure to thrive occurring in the first 18 months of life, followed by progressive liver failure and death by age 5 years. Although there have been two patients without apparent liver progression previously reported, no long-term follow-up clinical data have been available. We present here the clinical spectrum of the non-progressive liver form of GSD IV in four patients, and long-term follow-up of the oldest identified patients (ages 13 and 20 years). None has developed progressive liver cirrhosis, skeletal muscle, cardiac or neurological involvement, and none has been transplanted. Branching enzyme activity was also measured in cultured skin fibroblasts from patients with the classic liver progressive, the early neonatal fatal, and the non-progressive hepatic presentations of GSD IV. The residual branching enzyme activity in the patients without progression was not distinguishable from the other forms and could not be used to predict the clinical course. Our data indicate that GSD IV does not always necessitate hepatic transplantation and that caution should be used when counselling patients regarding the prognosis of GSD IV. Patients should be carefully monitored for evidence of progression before recommending liver transplantation.
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PMID:Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. 883 Jan 77

Type IV glycogenosis (polyglucosan body disease) is a rare congenital autosomal recessive inherited disorder, caused by lack of the branching enzyme (amylo-1,4-1,6 transglucosidase). This deficiency leads to storage of abnormal glycogen (polyglucosan bodies) in the liver and other tissues. The clinical onset of the disease is insidious with non-specific gastrointestinal symptoms followed by progressive hepatic failure. Usually patients die due to hepatic cirrhosis within 4 years. Sometimes myopathy of the heart and skeletal muscle is also present. In these cases, the clinical onset is often later than in typical cases. We report on two brothers with primarily cardiac manifestation and late onset of the disease. The older one started to suffer from progressive dilated cardiomyopathy at the age of 18 years, presenting with severe heart failure, hepatosplenomegaly, ascites and peripheral oedema. He also demonstrated myopathy and muscular atrophy especially of the shoulder and lower limbs. Initially he improved on medical therapy, but one year later severe heart failure recurred followed shortly afterwards by sudden cardiac death. Right heart and skeletal muscle biopsies were performed while he was alive. These, as well as the autopsy, revealed massive accumulation of polyglucosan bodies. In both heart and skeletal muscle, complete branching enzyme deficiency could be proven. His 14-year-old brother showed similar clinical findings of mild dilated cardiomyopathy. His muscle biopsy also revealed polyglucosan body myopathy. Thus, in young patients presenting with congestive cardiomyopathy, type IV glycogenosis has to be considered in the differential diagnosis.
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PMID:A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy. 888 67

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.
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PMID:Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. 898 49

Type III glycogen storage disease (GSD) is a disorder of carbohydrate metabolism caused by a deficiency of debranching enzyme. Different subtypes with different clinical pictures have been recognized. During childhood and early adulthood, the symptoms generally regress, and normal adulthood appears possible in most patients without symptoms or signs of cirrhosis. We report on an adult patient with GSD who developed endstage cirrhosis and a small hepatocellular carcinoma. She had GSD subtype IIIb, i.e., there were no signs of cardiomyopathy, myopathy, or neuropathy. She underwent a successful transplantation, representing the first case treated this way for this indication to our knowledge, and she is doing well after 1 year. Debranching enzyme activity was absent both in the liver and in the leukocytes before transplantation. The debranching enzyme activity remained absent in the leukocytes after transplantation. We conclude that patients with GSD type III may develop end-stage cirrhosis and hepatocellular carcinoma and therefore need hepatological follow-up during adulthood.
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PMID:Type IIIb glycogen storage disease associated with end-stage cirrhosis and hepatocellular carcinoma. The Liver Transplant Group. 904 94

Type IV glycogenosis or Andersen disease is characterized by a deficiency in branching enzyme. This rare disease is exceptionally seen at birth. The clinico-pathological data are then typical: severe hypotonia with hypoventilation and cellular storage, without any hepatosplenomegaly. The stored material is PAS positive, sometimes made of crystals and appeared birefringent under polarized light. Granulo-filamentous inclusions are shown by electron microscopy, essentially observed in muscle and liver without cirrhosis. Death occurs rapidly. The present case was typical. It is the eleventh reported case in the literature.
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PMID:[Congenital variant of type IV glycogenosis. Anatomoclinical report of a case]. 909 Sep 36

Mutations in three different genes of phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver. The autosomal-recessive, liver-specific variant of Phk deficiency is caused by mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit, PHKG2. To facilitate mutation detection and to improve our understanding of the molecular evolution of Phk subunit isoforms, we have determined the structure of the human PHKG2 gene. The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG2 and the gene of the muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatellite repeat, the first polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, in the two published cases of liver Phk deficiency who developed cirrhosis in childhood. As liver Phk deficiency is generally a benign condition and progression to cirrhosis is very rare, this finding suggests that PHKG2 mutations are associated with an increased cirrhosis risk.
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PMID:Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. 938 16

A 45-year-old woman with type IIIa glycogen storage disease (GSD IIIa) died of variceal hemorrhage secondary to liver cirrhosis. The postmortem examination disclosed increased intracellular glycogen in the liver as well as in the heart and skeletal muscle. Although most liver injuries in GSD IIIa have been considered to be non-progressive in adulthood, liver cirrhosis can be a cause of death in some patients.
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PMID:Fatal liver cirrhosis and esophageal variceal hemorrhage in a patient with type IIIa glycogen storage disease. 993 41

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.
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PMID:Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. 1060 21

Type III glycogen storage disease (GSD III) is an autosomal recessive disorder characterized by the accumulation of abnormal glycogen in the liver and, in most patients, in the muscle. Although liver fibrosis is a well-known consequence of GSD III, until now only eight cases of liver cirrhosis and two cases of hepatocellular carcinoma have been described in patients affected by this disease. In this case report, the authors describe the clinical history of a patient affected by GSD III who developed severe liver disease during her adult life, progressing from fibrosis to cirrhosis and finally to hepatocellular carcinoma. Until now, the hepatic involvement in GSD III has been considered by most authors as mild and almost always self-limiting. This report, together with the previously published cases, clearly indicates that severe and progressive liver disease may complicate this metabolic disorder. These observations advise a careful hepatologic follow-up of patients affected by GSD III.
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PMID:Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease. 1091 84

A 22-year-old woman without predisposing liver disease developed focal hepatic glycogenosis and hepatocellular carcinoma after 6 years of azathioprine therapy for Crohn's disease. Hepatocellular carcinoma without cirrhosis has previously been described during immunosuppression, but this is the first report of disseminated focal hepatic glycogenosis after long-term azathioprine therapy.
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PMID:Hepatocellular carcinoma and focal hepatic glycogenosis after prolonged azathioprine therapy. 1092 28


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