Other entities represented in this entry:CIRRHOSIS, FAMILIAL, WITH PULMONARY HYPERTENSION, INCLUDEDINDIAN CHILDHOOD CIRRHOSIS, INCLUDED; ICC, INCLUDEDSEN SYNDROM...
Other entities represented in this entry:
Aside from Wilson disease (277900), type IV glycogen storage disease (232500), and galactosemia (230400), which are well-known causes of familial cirrhosis, families with multiple affected sibs and normal parents have been observed (Iber and Maddrey, 1965). The group is probably heterogeneous and in some instances nongenetic factors may be responsible for the familial aggregation. Iber and Maddrey (1965) reviewed 13 reported families and 8 of their own, each with 2 or more affected members. They pointed out that with 1 exception the multiple cases were in the same generation. Within a given family, age of onset, clinical course, and biopsy findings were very similar, but there were wide differences between families. Baber (1956) described cases of congenital cirrhosis with generalized amino aciduria. Some of these patients may be examples of Wilson disease. Others may have tyrosinemia (Zetterstrom, 1963; Gentz et al., 1965). See tyrosinemia (276700). In India, so-called Indian childhood cirrhosis (Sen syndrome) affects multiple sibs (Chaudhuri and Chaudhuri, 1965). The disorder usually has its onset between ages 6 and 18 months and is said to be several times more frequent in males than in females; familial cases are frequent (Srivastava, 1956). Lefkowitch et al. (1982) described 4 white American sibs who died between ages 4.5 and 6 years of cirrhosis. Progressive lethargy, abdominal swelling, jaundice, and fever developed 4 to 7 months before death. The liver histopathology closely resembled that of the childhood cirrhosis of Asiatic Indians and included severe panlobular liver-cell swelling with Mallory body formation, prominent pericellular fibrosis, 'micro-micronodular' cirrhosis, and marked deposits of copper and copper-binding protein. Hepatic copper levels were as much as 40 times normal. The parents were apparently not related. The father was adopted. The mother, of Scottish and Irish extraction, had a single sib, a brother who died at the age of 10 years of cirrhosis. Copper-overload is a feature of the Indian childhood cirrhosis also. Before the report by Lefkowitch et al. (1982), the clinical syndrome had been described only in children in India, Pakistan, Sri Lanka, and Burma (Mowat, 1979) and rarely in immigrants to Britain from India (Tanner et al., 1978). The family history is said to be positive in about 30% of cases. Although one might suspect (in view of the population distribution) autosomal recessive inheritance with an occult selectively advantageous polymorphism in heterozygotes, no formal proof is available.
Kalra et al. (1982) studied the families of 220 cases of Indian childhood cirrhosis and 70 families of age-matched controls. The hypotheses of autosomal recessive, partial sex-linkage, and doubly recessive inheritance were found untenable. Multifactorial inheritance was found more plausible. In a review of the subject, Kumar (1984) concluded that multifactorial inheritance is likely. Gahl et al. (1988) pointed out that the use of brass cooking utensils in Indian families with ICC suggests an environmental source of copper toxicity; however, the 25% frequency of familial disease points to a genetic basis as well. Gahl et al. (1988) studied a 2-year-old boy with features of ICC whose parents were third cousins of European descent. He was normal at birth but had poor growth in infancy. At 18 months he developed nephrogenic diabetes insipidus. At 21 months liver enzymes were elevated and biopsy showed mild fibrosis and electron-dense granules, which electron probe analysis showed to contain sulfur and copper. By 29 months progressive liver failure and advanced micronodular cirrhosis with occasional Mallory bodies were found. The remaining hepatocytes stained strongly with rhodamine (for copper) and with orcein (for copper-binding proteins). The patient died at 32 months of an esophageal variceal bleed. The patient's disease was manifest in cultured fibroblasts. This may represent a lysosomal storage disorder. Yet another cause of congenital cirrhosis is alpha-1-antitrypsin deficiency (613490). Familial aggregation of chronic active hepatitis due to hepatitis B virus is discussed elsewhere (118900). The coincidence of liver disease and 'primary' pulmonary hypertension was indicated by 2 brothers in a family originally reported by Maddrey and Iber (1964), according to follow-up information from Summer and Herlong (1982); 3 brothers, 2 of them identical twins, were by then affected.
Muller et al. (1996) described 138 cases of endemic Tyrolean infantile cirrhosis (ETIC) which was clinically and pathologically indistinguishable from Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT) (Scheinberg and Sternlieb, 1996). It also resembled the early-onset form of Wilson disease. Although ETIC, ICC, and ICT require copper-enriched diets to become manifest (Tanner et al., 1983), it was thought that these disorders might represent allelic variants of Wilson disease. ETIC, like Wilson disease, shows autosomal recessive inheritance. In contrast to the 30 isolated cases described worldwide, the high frequency of ETIC in the Tyrol (Muller et al., 1996) suggested a founder effect. Wijmenga et al. (1998) published a pedigree with 11 affected children in 6 sibships, all of consanguineous parents and all with both parents tracing back to a common ancestral couple 10 generations ago. The lethality of the disease meant that no living children were available, but 8 pairs of parents were identified with at least 1 ETIC child. Wijmenga et al. (1998) studied the possible role of the ATP7B gene, mutant in Wilson disease, in ETIC by investigating association and haplotype sharing in obligate gene carriers. Haplotypes in ETIC carriers did not demonstrate sharing and the association studies did not detect linkage disequilibrium between ETIC and the individual markers at 13q14.3 where the ATP7B gene maps.
Muller et al. (1999) encountered 8 cases of infantile liver cirrhosis in 5 families in Emsland, a circumscribed and predominantly rural area of Northern Germany; ICT was definitely proven in 2 cases. Clinical presentation and liver pathology in 6 additional cases were consistent with the diagnosis of ICT. Pedigrees of affected families revealed complex relationships with occasional consanguinity of parents, suggesting autosomal recessive inheritance. The households were served by private wells with water of low pH flowing through copper pipes, suggesting the possibility of increased alimentary copper exposure. These findings supported an earlier conclusion that ICT develops when an infant with a genetic predisposition is exposed to a copper-enriched diet.
Pulmonary hypertension can develop as a complication of portal hypertension (Krowka, 1993). Hadengue et al. (1991) suggested that the pulmonary endothelial damage in this hepatopulmonary syndrome may be caused by nonmetabolized substances in the portal blood that reach the pulmonary vasculature through portal systemic shunting.
Patel and Parekh (1997) reported that parents and social workers observed an absence of rigor mortis for a minimum of 12 hours to a maximum of 30 hours postmortem in 37 children who died of ICC between the ages of 10 months and 2 years; the authors observed absence of rigor mortis for 22 to 36 hours after death in 5 hospitalized patients. Children who died from other causes developed body stiffness within 4 to 6 hours. Patel and Parekh (1997) noted that the absence of rigor mortis had not been mentioned in previous studies of ICC and postulated that excess glycogen in the muscles of these patients would facilitate postmortem ATP resynthesis and so delay the development of rigor.