Cholesteryl ester storage disease
Encyclopedia
Cholesteryl Ester Storage Disease (CESD) is the late onset phenotype for Lysosomal Acid Lipase (LAL) Deficiency, a Lysosomal storage disease
, which also has an early onset phenotype known as Wolman disease
that primarily affects infants. CESD can present in childhood but often goes unrecognized until adulthood when the underlying pathology
is advanced. Many of the signs and symptoms are common to patients with other liver conditions.
CESD is an autosomal recessive genetic condition and is characterized by hepatomegaly
, persistently abnormal LFTs and type II hyperlipidemia
. Splenomegaly
and evidence of mild hypersplenism may affect some patients. Untreated, CESD may lead to fibrosis
, cirrhosis
, liver failure and death.
Disease Risk In Families:
• 25 per million incidence
• Autosomal recessive disorder, LAL deficiency is carried on chromosome 10
• Parents with an affected son or daughter have a 1 in 4 chance of having another affected child
and triglyceride
levels (type II hyperlipidemia) and may present at an early age with the following liver abnormalities:
• Unexplained hepatomegaly
• Elevated transaminases
• Unexplained fatty liver
• Progressive and/or unexplained chronic liver disease
Type II hyperlipidemia
in association with unexplained fatty liver or elevated transaminases in more than one sibling in a family would warrant consideration of a diagnosis of CESD.
Patients with CESD are typically investigated for infectious, metabolic and autoimmune liver disease. Imaging may suggest hepatic steatosis and liver biopsies when performed show accumulation of fat in hepatocytes and Kupffer cells. Periportal fibrosis and cirrhosis
is not uncommon. Descriptive terms including sea blue Histiocytosis may be applied to the liver abnormalities.
Useful Diagnostic Clues
• Low normal High-density lipoprotein (HDL)(<10th percentile or <35 mg/dL for men and women), especially very low HDL (<5-10 mg/dL)
• Excessive hepatomegaly and/or transaminase increase for a given BMI
• Unusual coexisting lymphadenopathy
or enlarged lymph nodes
• Onset of liver abnormalities in childhood
• Clinical suspicion of visceral Niemann Pick not confirmed by enzyme analysis
• An enlarged spleen that is disproportionate in size to the degree of liver involvement/disease
Other Manifestations
• Short stature
• Premature cardiac disease
• Premature stroke
• Malabsorption
Challenges in Diagnosis
Cholesteryl Ester Storage Disease (CESD) is rare and can be difficult to diagnose. Recent studies using genetic analysis suggest that heterozygote carriers of a common disease causing mutation for CESD are more common than previously thought with a carrier frequency for this mutation of about 1 in 200 or 5000 per million. Based on these carrier frequencies and the mutation spectrum of published CESD cases this translates to an estimate of approximately 25 cases of CESD per million births.
Delayed diagnosis may be the result of disease under-recognition and/or symptoms being mistaken for those of other disorders, such as:
• Non Alcoholic Fatty Liver Disease (NAFLD)
• Non Alcoholic Steatohepatitis (NASH)
• Alcoholic Liver Disease
• Cryptogenic Cirrhosis
Clinical diagnosis is based upon presentation of signs, symptoms and laboratory abnormalities (lipids, liver transaminases) and may be confirmed by enzyme assay (blood test) detecting low or absent levels of lysosomal acid lipase or in relatives of affected patients by mutation linkage analysis (blood test).
with a low cholesterol diet has been effective at reducing some of the symptoms associated with this genetic disorder
.
Synageva BioPharma Corp. of Lexington, Massachusetts, is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency. For more information, refer to the Synageva.com.
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
, which also has an early onset phenotype known as Wolman disease
Wolman disease
Wolman Disease Wolman Disease Wolman Disease (also known as Wolman’s Disease, early onset LAL Deficiency, and Lysosomal acid lipase deficiency is a rare genetic disorder caused by a deficiency of an enzyme known as lysosomal acid lipase (LAL or LIPA). This enzyme is necessary to break down certain...
that primarily affects infants. CESD can present in childhood but often goes unrecognized until adulthood when the underlying pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
is advanced. Many of the signs and symptoms are common to patients with other liver conditions.
CESD is an autosomal recessive genetic condition and is characterized by hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
, persistently abnormal LFTs and type II hyperlipidemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
. Splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
and evidence of mild hypersplenism may affect some patients. Untreated, CESD may lead to fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, liver failure and death.
Disease Risk In Families:
• 25 per million incidence
• Autosomal recessive disorder, LAL deficiency is carried on chromosome 10
• Parents with an affected son or daughter have a 1 in 4 chance of having another affected child
Diagnosis and Testing
Patients with Cholesteryl Ester Storage Disease typically have elevated cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels (type II hyperlipidemia) and may present at an early age with the following liver abnormalities:
• Unexplained hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
• Elevated transaminases
• Unexplained fatty liver
• Progressive and/or unexplained chronic liver disease
Chronic liver disease
Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis.- Causes :...
Type II hyperlipidemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
in association with unexplained fatty liver or elevated transaminases in more than one sibling in a family would warrant consideration of a diagnosis of CESD.
Patients with CESD are typically investigated for infectious, metabolic and autoimmune liver disease. Imaging may suggest hepatic steatosis and liver biopsies when performed show accumulation of fat in hepatocytes and Kupffer cells. Periportal fibrosis and cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
is not uncommon. Descriptive terms including sea blue Histiocytosis may be applied to the liver abnormalities.
Useful Diagnostic Clues
• Low normal High-density lipoprotein (HDL)(<10th percentile or <35 mg/dL for men and women), especially very low HDL (<5-10 mg/dL)
• Excessive hepatomegaly and/or transaminase increase for a given BMI
• Unusual coexisting lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
or enlarged lymph nodes
• Onset of liver abnormalities in childhood
• Clinical suspicion of visceral Niemann Pick not confirmed by enzyme analysis
• An enlarged spleen that is disproportionate in size to the degree of liver involvement/disease
Other Manifestations
• Short stature
• Premature cardiac disease
• Premature stroke
• Malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
Challenges in Diagnosis
Cholesteryl Ester Storage Disease (CESD) is rare and can be difficult to diagnose. Recent studies using genetic analysis suggest that heterozygote carriers of a common disease causing mutation for CESD are more common than previously thought with a carrier frequency for this mutation of about 1 in 200 or 5000 per million. Based on these carrier frequencies and the mutation spectrum of published CESD cases this translates to an estimate of approximately 25 cases of CESD per million births.
Delayed diagnosis may be the result of disease under-recognition and/or symptoms being mistaken for those of other disorders, such as:
• Non Alcoholic Fatty Liver Disease (NAFLD)
• Non Alcoholic Steatohepatitis (NASH)
• Alcoholic Liver Disease
Alcoholic liver disease
Alcoholic liver disease is a term that encompasses the hepatic manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis or cirrhosis. It is the major cause of liver disease in Western countries...
• Cryptogenic Cirrhosis
Clinical diagnosis is based upon presentation of signs, symptoms and laboratory abnormalities (lipids, liver transaminases) and may be confirmed by enzyme assay (blood test) detecting low or absent levels of lysosomal acid lipase or in relatives of affected patients by mutation linkage analysis (blood test).
Treatment
There is no disease modifying treatment for Cholesteryl Ester Storage Disease (CESD). Combining drugs that reduce blood cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
with a low cholesterol diet has been effective at reducing some of the symptoms associated with this genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
.
Synageva BioPharma Corp. of Lexington, Massachusetts, is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency. For more information, refer to the Synageva.com.