Liver disease inherited disorders

These dru are contraindicated in patients with known hypersensitivity. Hydroxychloroquine is contraindicated in patients with porphyria (a group of serious inherited disorders affecting the bone marrow or the liver), psoriasis (chronic skin disorder), and retinal disease (may cause irreversible retinal damage). MTX is contraindicated during pregnancy because it is a Pregnancy Category X dmg and may cause birth defects... 

Although chelation is not helpful for Alzheimer s disease patients, it is the key to treating patients with dementia due to Wilson s disease. Wilson s disease is a genetically inherited disorder that usually strikes before age 30. The disease causes toxic levels of copper to accumulate in the liver, brain, eyes, and kidney. Untreated, Wilson s disease leads to tremors, cirrhosis, depression, psychosis, dementia, and ultimately death. Chelation with penicillamine (Cuprimine) can stop and even reverse the accumulation of copper. 

Zinc is used for a variety of indications. Zinc acetate (8.102) or, rarely, zinc sulfate (8.103) have been used orally to treat Wilson s disease, a recessively inherited disorder of copper metabolism, characterized by brain and liver dysfunction arising from excessive deposits of copper. Zinc pyrithione (8.104) is used in shampoos to treat seborrhea. Zinc propionate (8.105) and zinc caprylate (8.106) have been used as topical antifungal agents. 

Wilson s disease, an autosomally recessively inherited disorder, is due to a defect in copper metabolism which leads to an accumulation of the element in the liver. A subse-... 

Wilson s disease is an inherited disorder of copper metabolism. Copper accumulates initially in the liver and then in the nervous system, leading to severe liver and neurological disease. The retention of copper begins at birth, but it may take decades before the liver is sufficiently damaged... 

Table 3.5 Examples of inherited and metabolic disorders resulting in liver disease...

The disease is a rare inherited disorder characterized by a progressive degeneration of the lenticular nucleus in the brain and by cirrhosis of the liver. Barbeau et al. (Bl) studied a case of Wilson s disease which presented normal ceruloplasmin and serum copper values but increased excretion of kynurenine, 3-hydroxykynurenine, and conjugated anthra-nilic acid in xurine after an oral dose of 2 g L-tryptophan. This defect in tryptophan metabolism could be related to that of other amino acids and to the actual content of ceruloplasmin in Wilson s disease (Bl). These findings corroborated Marver s (M2) investigations demonstrating a definite excretion of kynurenine and 3-hydroxykynurenine in abnormal proportions after a tryptophan load in a case of Wilson s disease. 

Wilson s disease is an autosomal recessive inherited disorder of copper metabolism resulting in accumulation of copper in various tissues. Rats raised to have a large accumulation of copper had 80 times greater concentration of MTs in their liver compared to controls (5016pgg vs. 65pgg ). 

The fasting venous plasma ammonia concentration is useful in the differential diagnosis of encephalopathy when it is unclear if encephalopathy is of an hepatic origin. It is especially helpful in diagnosing Reye s syndrome and the inherited disorders of urea metabolism. However, it is not a useful test to use in patients with laiown liver disease. 

Serial measurement of bilirubin is helpful in measuring the severity of liver disease. Bhirubiti fractionation is helpfiil only in jaundice of the newborn or in isolated elevations of bilirubin in the absence of other Uver test abnormalities that would indicate an inherited disorder of bilirubin metabolism. 

In another rare inherited disorder, called Wilson s disease, excessive amounts of copper accumulate in liver and brain tissue. A prominent symptom of the disease is the deposition of copper in greenish-brown layers surrounding the cornea, called Kayser-Fleischer rings. Wilson s disease is now known to be caused by a defective ATP-dependent protein that transports copper across cell membranes. Apparently, the copper transport protein is required to incorporate copper into ceruloplasmin and to excrete excess copper. In addition to a low copper diet, Wilson s disease is treated with zinc sulfate and the chelating agent penicillamine (p. 123). Describe how these treatments work. (Hint Metallothionein has a greater affinity for copper than for zinc.)... 

Wilson s disease (WD hepato-lenticular degeneration), is a rare, often familial, progressive disease of the central nervous system (CNS) and the liver, due to disordered copper metabolism. WD is an autosomal recessive inherited disease which occurs worldwide and has a remarkably uniform prevalence of about 30 per one million... 

Tyrosyluria (the excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyl-lactate and 4-hydroxyphenylacetate with hypertyrosinaemia) occurs in some normal newborn babies, particularly premature babies, scurvy (ascorbate or vitamin C deficiency), tyrosinosis (Medes, 1932), hepatic cytosol tyrosine transaminase deficiency (oculo-cutaneous tyrosinaemia) (Kennaway and Buist, 1971), in hereditary tyrosinaemia ( inborn hepatorenal dysfunction with tryosyluria ) (LaDu and Gjessing, 1978) and as a secondary phenomenon to a number of liver diseases, including several inherited metabolic diseases unassociated directly with tyrosine metabolism (for example, propionic acidaemia) or involving disorders of carbohydrate metabolism (for example, galactosaemia and fructosaemia). 

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in liver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa (USEPA 1980 Aaseth and Norseth 1986). Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive... 

Vitamin D deficiency remains the most common cause of rickets and osteomalacia in the world, with the exception of the United States and the Scandinavian countries where most dairy products are supplemented with this vitamin. This deficiency can be caused either by dietary habits or by insufficient exposure to ultraviolet light. The same type of symptoms can be observed when there is interruption of the normal vitamin D metabolic pathways due to a number of liver and/or kidney diseases. In addition, a number of inherited factors can lead to different types of vitamin D resistance which require massive supplements of vitamin D and/or minerals. Extensive reviews have been published depicting both the clinical features and their most likely causes, as well as the possible treatments of the different types of clinical disorders resulting from vitamin D deficiencies [113-117], The newly defined role for l,25(OH)2D3 upon the hematopoietic system could also have clinical relevance in bone disorders such as osteoporosis where patients have been shown to possess abnormal T-cell subsets [118]. 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

Another metabolic disorder that is hereditary and little known is hypophosphatasia. Hypophosphatasia is an inherited metabolic (chemical) bone disease that results from low levels of an enzyme called alkaline phosphatase (ALP). ALP is normally present in large amounts in bones and the liver. In hypophosphatasia, abnormalities in the gene that makes ALP lead to the production of inactive ALP. Subsequently, several chemicals, including phosphoethanolamine, pyridoxal 57-phosphate (a form of vitamin B ) and inorganic pyrophosphate, accumulate in the body and are found in large amounts in the blood and urine. It appears that the accumulation of inorganic pyrophosphate is the cause of the characteristic defective calcification of bones seen in infants and children (rickets) and in adults (osteomalacia). 

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