Guide
Rare diseases, also known as orphan diseases, have relatively few patients. The definition of rare diseases varies from region to region, and in mainland China, rare diseases refer to diseases with a prevalence of less than 1/500,000 in the population or less than 1/10,000 in newborns.
It is estimated that there are about 16.8 million patients with rare diseases in mainland China, and in order to help clinicians better understand these rare diseases, this article summarizes 5 rare diseases in the Department of Hepatology for readers.
First, Wilson's disease
Wilson's disease, also known as Wilson's disease (WD), is an autosomal recessive disorder. ATP7B gene mutation leads to the transport and excretion of copper ions in the body, and copper accumulates in the liver, nervous system, cornea, kidney and other organs, resulting in a series of clinical manifestations.
WD occurs mainly in children and adolescents and can affect multiple organs throughout the body. Children tend to have liver involvement as the first manifestation, and adolescents and adults have neurological involvement as the first symptom. Hepatic lesions can present with persistent elevation of asymptomatic aminotransferases, chronic hepatitis, cirrhosis, and acute liver failure. Neurological involvement can be manifested as motor dysfunction, tremor, ataxia, etc., and some patients have psychobehavioral abnormalities. Other systems affected include the kidneys, blood system, osteoarticular, cardiac, endocrine, and reproductive systems.
Figure 1 WD diagnosis and treatment process
Second, hereditary hemochromatosis
Hereditary hemochromatosis (HH) is an autosomal recessive disease, more common in men, caused by congenital excessive deposition of iron in liver cells, pancreatic epithelial cells, cardiomyocytes, joint soft tissue cells, etc., causing corresponding organ damage.
HH first affects the liver, and on MRI it is mainly manifested as "black liver sign". Then the pancreas, then the myocardium, and finally the joints are involved, and multi-organ complications such as the heart, liver, pancreas, thyroid, gonads, skin and joints occur, including skin pigmentation, hepatomegaly and cirrhosis, diabetes, decreased libido and testicular atrophy, hypothyroidism, joint lesions, etc.
Figure 2 HH diagnosis and treatment process
3. Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders. Gene mutations lead to impaired bile excretion, intrahepatic cholestasis, and eventually liver failure. According to different pathogenic genes, PFIC is mainly divided into 3 types, including PFIC-1, PFIC-2 and PFIC-3.
PFIC typically presents with jaundice and pruritus. Other symptoms include developmental delays such as short stature and delayed puberty, gallstones, steatorrhea due to fat absorption disorders, hepatosplenomegaly, rickets due to fat-soluble vitamin deficiency, bone age delay, dry eye, coagulopathy, and neuromuscular lesions.
The diagnosis of PFIC depends on clinical manifestations, blood biochemistry (blood conjugated bilirubin, alkaline phosphatase and bile acid are increased to varying degrees, blood cholesterol is normal, PFIC-3 type has elevated blood glutamyl transpeptidase), bile composition analysis, liver histopathological examination and genetic testing, and other causes of cholestatic liver disease need to be excluded.
Treatment of PFIC includes symptomatic treatment (vitamin supplementation, medium-chain triglycerides, etc., to improve nutritional status), drug therapy [ursodeoxycholic acid 10~30 mg/(kg·d)], surgical treatment (bile shunting), and liver transplantation.
4. Congenital bile acid synthesis disorders
Congenital disorders of bile acid synthesis (IEBAS) are congenital disorders of bile acid synthesis due to genetic defects in enzymes necessary for the synthesis of the two main bile acids. IEBAS is a class of autosomal stealth genetic disorders.
The clinical manifestations of IEBAS are progressive cholestatic liver disease, neurological lesions and fat-soluble vitamin malabsorption. Diagnosis is based on clinical symptoms, laboratory tests (conjugated bilirubin, aminotransferase, normal γ glutamate transpeptidase), ancillary tests, and pathologic biopsy, and confirmation depends on urinary bile acid testing and genetic testing.
For the treatment of IEBAS, liver transplantation is often indicated if severe liver damage has occurred at the time of diagnosis; If there is no serious liver damage, follow the principle of individualized treatment, supplement the primary bile acids, judge the efficacy according to the abnormal metabolite content in the urine, and adjust the treatment.
5. Homozygous familial hypercholesterolemia
Familial hypercholesterolemia (FH) is an inherited disorder caused by mutations in one of the key genes for the catabolism of low-density lipoprotein cholesterol (LDL-C). Homozygous familial hypercholesterolemia (HoFH) is caused by homozygous mutations or compound heterozygous mutations in these key genes.
The main clinical manifestations of HoFH include markedly elevated LDL-C levels immediately after birth, cholesterol deposits in the skin, eyes, and tendons to form xanthomas and lipogenic corneal arches.
Diagnosis of HoFH is based on genetic and clinical criteria.
- Genetic diagnostic criteria: Two alleles are found to have mutations in the LDLR, APOB, PCSK9 or LDLRAP1 gene loci through genetic testing.
- Clinical diagnostic criteria: LDL-C > 500 mg/dl (>13 mmol/L) or LDL-C >300 mg/dl (>8 mmol/L) after treatment and one of the following: skin or tendon xanthoma before 10 years of age; Parental LDL-C levels are elevated and meet the criteria for heterozygous FH.
Treatment of HoFH includes a healthy lifestyle (low saturated fat, low cholesterol, heart-healthy diet recommended), medications (mainly statins, which can be combined with other cholesterol-lowering drugs), lipoprotein plasma clearance, liver transplantation, and other surgical treatments.
Bibliography:
[1] Lv T, Jia J. Rare liver diseases are not rare in China[J]. Liver Int. 2022 Apr 1. doi: 10.1111/liv.15267.
[2] Guidelines for the diagnosis and treatment of rare diseases (2019 edition).
[3] XU Wenjiao, LI Changping, SHI Lei. Clinical features and diagnosis and treatment progress of hemochromatosis[J]. Modern Clinical Medicine, 2019,45(04):303-306.
Jin Jinglan, Zhao Xu, Li Guangming, et al. Key points of the American Association of Hepatology guidelines for the diagnosis and treatment of hemochromatosis[J]. Journal of Clinical Hepatobiliary Diseases, 2013,29(05):403-405.