Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications. In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth. Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for prophylaxis therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.

In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses. Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports, guidelines set by the United Kingdom, and expert opinions rather than controlled clinical studies.

Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a close blood relative of such an individual. Initial laboratory findings include a decrease in serum fibrinogen mass levels as measured by immunoassay plus a reduction in inducible blood clot formation so that the ratio of functionally-detected fibrinogen mass (i.e. detected in induced clots) to immunoassay-detected fibrinogen mass is abnormally low, i.e. <0.7. This contrast with individuals with congenital dysfibrinogenemia who exhibit normal levels of fibrinogen as measured by immunoassay but low functionally-detected to immunoassay-detected fibrinogen mass ratios, i.e. <0.7. Where available, specialized laboratories can conduct studies to define the exact gene mutation(s) and fibrinogen abnormalities underlying the disorder.

The diagnosis of hypofibrinogenemia is indicated in individuals who have low levels (<1.5 gram/liter) of plasma fibrinogen as determined by both immunological (e.g. immunoelectrophoresis and (i.e. able to be clotted) methods. The ratio of immunological to functional fibrinogen masses should be ~1.0 as assayed with partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests. These tests are used to distinguish hypofibrinogenemia from hypodysfibrinogenemia, a typically more severe disorder in which plasma fibrinogen levels are low and this fibrinogen includes at least in part dysfunctional fibrinogen. Immunological/functional fibrinogen ratios for the plasma of individuals with hypodysfibrinogenemia for all the cited tests are usually <0.7. Where available, further analyses are recommended; these include analyses of the fibrinogen genes and protein chains for mutations and specialized studies of individuals in vitro induced blood clots for stability and susceptibility to lyses.

The diagnosis of fibrin storage disease requires liver biopsy and the finding of immunologically detectable fibrinogen inclusion bodies in hepatocytes.

Blood relatives of the proband case should be evaluated for the presence of hypodysfibrinogenemia. Individuals with the disorder need to be advised on its inheritance, complications, and preventative measures that can be taken to avoid bleeding and/or thrombosis. Since >80% of individuals may develop bleeding or thrombosis complications of the disorder, asymptomatic individuals diagnosed with hydposyfibrinogenemia are best handled at a specialized center in order to benefit from multidisciplinary management.

Measures to prevent and/or treat complications of hypodysfibrinogenemia should be tailored to the personal and family history of the individual by a specialized center. Individuals with a personal or family history of bleeding are considered to be of low risk of bleeding when their functional fibrinogen levels are >1 gram/liter for major surgery, >0.5 gram/liter for minor surgery, >0.5 to 1-2 gram/liter for spontaneous bleeding (depending on its severity), >0.5 to > 1 gram/liter for the first two trimesters of pregnancy, and >1 to <2 gram/liter for the last trimester of pregnancy and postpartum period. Functional fibrinogen below these levels should be treated preferably with fibrinogen concentrate or if not available, fibrinogen-rich cryoprecipitate or plasma to attain low risk levels of functional fibrinogen. Antifibrinolytic drugs such as tranexamic acid or (ε-aminocaproic acid) may be considered as an alternative preventative or therapeutic treatments in cases of minor surgery, dental extractions, mucosal bleeding, or other episodes of mild bleeding. In individuals with a personal or family history of thrombosis, should be considered for long-term anticoagulation drugs such as low molecular weight heparin, coumadin, or rivaroxaban.

Recommended treatment of asymptomatic congenital hypofibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as indicated by the personal history of the afflicted individual and family members. Where possible, determination of the exact mutation causing the disorder and the propensity of this mutation type to develop these complications may be helpful. Individuals with fibrinogen levels >1.0 gram/liter typically do not develop bleeding or thrombosis episodes. Individuals with fibrinogen levels of 0.5-1.0 grams/liter require fibrinogen supplementation preferably with a plasma-derived fibrinogen concentrate to maintain fibrinogen levels of >1 gram/liter prior to major surgery. Individuals with fibrinogen levels of 1 to 2 gram/liter at the end of pregnancy and during the postpartum period; b) > 1 gram/liter prior to major surgery; c) > 0.5 to 1 gram/liter during the first two trimesters of pregnancy; and d) >0.5 gram/liter prior to minor surgery. Tranexamic acid may be used in place of fibrinogen supplementation as prophylactic treatment prior to minor surgery and to treat minor bleeding episodes.

Fibrinogen disorders are set of hereditary or acquired abnormalities in the quantity and/or quality of circulating fibrinogens. The disorders may lead to pathological bleeding and/or blood clotting or the deposition of fibrinogen in the liver, kidneys, or other organs and tissues. These disorders include:

- Congenital afibrinogenemia, an inherited blood disorder in which blood does not clot normally due to the lack of fibrinogen; the disorder causes abnormal bleeding and thrombosis.

- Congenital hypofibrinogenemia, an inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen; the disorder may cause abnormal bleeding and thrombosis.

- Fibringogen storage disease, a form of congenital hypofibrinogenemia in which specific hereditary mutations in fibrinogen cause it to accumulate in, and damage, liver cells. The disorder may lead to abnormal bleeding and thrombosis but also to cirrhosis.

- Congenital dysfibrinogenemia, an inherited disorder in which normal levels of fibrinogen composed at least in part of a dysfunctional fibrinogen may cause abnormal bleeding and thrombosis.

- Hereditary fibrinogen Aα-Chain amyloidosis, a form of dysfibrinogenemia in which certain fibrinogen mutations cause blood fibrinogen to accumulate in the kidney and cause one type of familial renal amyloidosis; the disorder is not associated with abnormal bleeding or thrombosis.

- Acquired dysfibrinogenemia, a disorder in which normal levels of fibrinogen are composed at least in part of a dysfunctional fibrinogen due to an acquired disorder (e.g. liver disease) that leads to the synthesis of an incorrectly glycosylated (i.e. wrong amount of sugar residues) added to an otherwise normal fibrinogen. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting.

- Congenital hypodysfibrinogenemia, an inherited disorder in which low levels of fibrinogen composed at least in part of a dysfunctional fibrinogen may cause pathological episodes of bleeding or blood clotting.

- Cryofibrinogenemia, an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen, fibrin, and other circulating proteins thereby causing the infarction of various tissues and bodily extremities.

Suggested diagnostic criteria for cryoglobulinemic disease fall into the following obligatory and additional categories:

- Obligatory criteria: 1) cold sensitivity; 2) cutaneous symptoms (i.e. urticaria, purpura, Raynaud phenomenon, ulceration/necrosis/gangrene, and/or livedo reticularis); 3) arterial and/or venous thrombotic events; fever; 4) arthralgia/myalgia; 5) neuritis in >1 site; and 6) renal disorder.

- Additional criteria: 1) typical biopsy findings at site(s) of involvement and 2) angiogram evidence of occlusion in one or more small to medium sized arteries.

The diagnosis of secondary cryofibrinogenemia also requires evidence for the cited infectious, malignant, premalignant vasculitis, and autoimmune disorders while the diagnosis of primary cryofibriongenemia requires a lack of evidence for 1) the cited associated disorders, 2) other vascular occlusive diseases, and 3) cryoglobulinemia.

Studies on the treatment of cryofibrinoginemic disease have involved relatively few patients, are limited primarily to case reports, and differ based on whether the disease is primary or secondary. In all cases of cryofibrinogenemic disease, however, patients should avoid the exposure of afflicted body parts to cold weather or other environmental triggers of symptoms and avoid using cigarettes or other tobacco products. In severe cases, these individuals also risk developing serious thrombotic events which lead to tissue necrosis that may result in secondary bacterial infections and require intensive antimicrobial therapy and/or amputations. Careful treatment of these developments is required.

Definitive diagnosis requires LCAT gene analysis for mutation and functional activity. However, numerous lab tests may help with making a diagnosis such as complete blood count (CBC), urinalysis, blood chemistries, lipid panels, and plasma LCAT activity.

Fish-eye disease is characterized by abnormalities like visual impairment, plaques of fatty material, and dense opacification.

Renal failure is the major cause of morbidity and mortality in complete LCAT deficiency, while in partial deficiency (fish eye disease) major cause of morbidity is visual impairment due to corneal opacity. These patients have low HDL cholesterol but surprisingly premature atherosclerosis is not seen. However, there are some reported cases.

Familial LPL deficiency should be considered in anyone with severe hypertriglyceridemia and the chylomicronemia syndrome. The absence of secondary causes of severe hypertriglyceridemia (like e.g. diabetes, alcohol, estrogen-, glucocorticoid-, antidepressant- or isotretinoin-therapy, certain antihypertensive agents, and paraproteinemic disorders) increases the possibility of LPL deficiency. In this instance besides LPL also other loss-of-function mutations in genes that regulate catabolism of triglyceride-rich lipoproteins (like e.g. ApoC2, ApoA5, LMF-1, GPIHBP-1 and GPD1) should also be considered

The diagnosis of familial lipoprotein lipase deficiency is finally confirmed by detection of either homozygous or compound heterozygous pathogenic gene variants in "LPL" with either low or absent lipoprotein lipase enzyme activity.

Lipid measurements

· Milky, lipemic plasma revealing severe hyperchylomicronemia;

· Severely elevated fasting plasma triglycerides (>2000 mg/dL);

LPL enzyme

· Low or absent LPL activity in post-heparin plasma;

· LPL mass level reduced or absent in post-heparin plasma;

Molecular genetic testing

The LPL gene is located on the short (p) arm of chromosome 8 at position 22. More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency so far.

Testing the general population under the age of 40 without symptoms is of unclear benefit.

Apolipoprotein B deficiency (also known as "Familial defective apolipoprotein B-100") is an autosomal dominant disorder resulting from a missense mutation which reduces the affinity of apoB-100 for the low-density lipoprotein receptor (LDL Receptor) . This causes impairments in LDL catabolism, resulting in increased levels of low-density lipoprotein in the blood. The clinical manifestations are similar to diseases produced by mutations of the LDL receptor, such as familial hypercholesterolemia. Treatment may include, niacin or statin or ezetimibe.

It is also known as "normotriglyceridemic hypobetalipoproteinemia".

The U.S. Preventive Services Task Force in 2008 strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease. In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.

In Canada, screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels, screening is recommended once every five years. Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.

The blood count typically shows decreased numbers of blood cells—including a decreased amount of circulating red blood cells, white blood cells, and platelets.

The bone marrow may show hemophagocytosis.

The liver function tests are usually elevated. A low level of the protein albumin in the blood is common.

The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients.

The serum fibrinogen level is usually low and the D-dimer level is elevated.

The sphingomyelinase is elevated.

Bone marrow biopsy shows histiocytosis.

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

Treatment of LPLD has two different objectives: immediate prevention of pancreatitis attacks and long term reduction of cardiovascular disease risk. Treatment is mainly based on medical nutrition therapy to maintain plasma triglyceride concentration below 11,3 mmol/L (1000 mg/dL). Maintenance of triglyceride levels below 22,6 mmol/L (2000 mg/dL) prevents in general from recurrent abdominal pain.

Strict low fat diet and avoidance of simple carbohydrates

Restriction of dietary fat to not more than 20 g/day or 15% of the total energy intake is usually sufficient to reduce plasma triglyceride concentration, although many patients report that to be symptom free a limit of less than 10g/day is optimal. Simple carbohydrates should be avoided as well. Medium-chain triglycerides can be used for cooking, because they are absorbed into the portal vein without becoming incorporated into chylomicrons. Fat-soluble vitamins A, D, E, and K, and minerals should be supplemented in patients with recurrent pancreatitis since they often have deficiencies as a result of malabsorption of fat. However, the diet approach is difficult to sustain for many of the patients.

Lipid lowering drugs

Lipid-lowering agents such as fibrates and omega-3-fatty acids can be used to lower TG levels in LPLD, however those drugs are very often not effective enough to reach treatment goals in LPLD patients. Statins should be considered to lower elevated non-HDL-Cholesterol.

Additional measures are avoidance of agents known to increase endogenous triglyceride levels, such as alcohol, estrogens, diuretics, isotretinoin, anidepressants (e.g. sertraline) and b-adrenergic blocking agents.

Gene therapy

In 2012, the European Commission approved alipogene tiparvovec (Glybera), a gene therapy for adults diagnosed with familial LPLD (confirmed by genetic testing) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It was the first gene therapy to receive marketing authorization in Europe; it was priced at about $1 million per treatment, and as of 2016, only one person had been treated with it.

Both conditions are treated with fibrate drugs, which act on the peroxisome proliferator-activated receptors (PPARs), specifically PPARα, to decrease free fatty acid production. Statin drugs, especially the synthetic statins (atorvastatin and rosuvastatin), can decrease LDL levels by increasing hepatic reuptake of LDL due to increased LDL-receptor expression.

Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis", have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis is found.

For treatment of type II, dietary modification is the initial approach, but many patients require treatment with statins (HMG-CoA reductase inhibitors) to reduce cardiovascular risk. If the triglyceride level is markedly raised, fibrates (peroxisome proliferator-activated receptor-alpha agonists) may be preferable due to their beneficial effects. Combination treatment of statins and fibrates, while highly effective, causes a markedly increased risk of myopathy and rhabdomyolysis, so is only done under close supervision. Other agents commonly added to statins are ezetimibe, niacin, and bile acid sequestrants. Dietary supplementation with fish oil is also used to reduce elevated triglycerides, with the greatest effect occurring in patients with the greatest severity. Some evidence exists for benefit of plant sterol-containing products and omega-3 fatty acids.

Biochemical markers include a normal GGT for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid levels are grossly elevated. Serum cholesterol levels are typically not elevated, as is seen usually in cholestasis, as the pathology is due to a transporter as opposed to an anatomical problem with biliary cells.

Familial dysbetalipoproteinemia or type III hyperlipoproteinemia (also known as remnant hyperlipidemia, "remnant hyperlipoproteinaemia", "broad beta disease" and "remnant removal disease") is a condition characterized by increased total cholesterol and triglyceride levels, and decreased HDL levels.

This condition is caused by a mutation in apolipoprotein E (ApoE), that serves as a ligand for the liver receptors for chylomicrons, IDL and VLDL or Very Low Density lipoprotein receptors. The normal ApoE turns into the defective ApoE2 form due to a genetic mutation. This defect prevents the normal metabolism of chylomicrons, IDL and VLDL, otherwise known as remnants, and therefore leads to accumulation of cholesterol within scavenger cells (macrophages) to enhance development and acceleration of atherosclerosis.

Clinical features along with the familial tendency may be enough to make a diagnosis. Genetic testing may also be used.