The Acute Porphyrias, and other Contraindications for Very Low Carbohydrate Diets and Fasting.

From the Department of Due Diligence...

Contraindications for Ketogenic and Very Low Carbohydrate Diets

This list of medical conditions which may cause adverse reactions to ketogenic diets or fasting may not be complete and is intended to be updated as necessary.

Acute Intermittent Porphyria and Acute Variegate Porphyria

The possibility of uncovering undiagnosed cases of these related disorders should always be borne in mind by those prescribing or experimenting with carbohydrate-restricted diets or fasting.

Acute Intermittent Porphyria (AIP) - Genetic disorder of incomplete heme synthesis due to deficiency of porphobilinogen deaminase with incidence 5-10 per 100,000.

 Acute Variegated Porphyria (AVP) - Genetic disorder reducing heme synthesis by 50% due to mutation of protoporphyrinogen oxidase, with incidence 1 in 300 (South Africa) to 1 in 75,000 (Finland).

True incidence may be greater as some cases are only diagnosed when triggered by low-carbohydrate diets or fasting.

- Some new cases of AIP and AVP were diagnosed at the height of Atkins diet popularity in the 1970s and this can be expected to recur during current popularity of LCHF diets.[1]

Symptoms may include:

Abdominal pain which is severe and poorly localized (most common, 95% of patients experience)
Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine)
(Note: urine turning dark after exposure to sunlight or UV light is useful diagnostic sign)
Peripheral neuropathy (patchy numbness and paresthesias)
Proximal motor weakness (usually starting in upper extremities which can progress to include respiratory impairment and death)
Autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia, hypertension, sweating, restlessness and tremor)
Neuropsychiatric symptoms (anxiety, agitation, hallucination, hysteria, delirium, depression)
Electrolyte abnormalities (Hyponatremia may be due to hypothalamic involvement leading to SIADH that may lead to seizures).
AIP can also present as acute pancreatitis [2, 3, 4]

Rash is not typically seen in AIP, but in AVP skin can be overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.

Patients with acute porphyrias are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphobilinogen, thus aggravating the disease enough that it may prove fatal.

10% glucose infusion or high-carbohydrate diet used in treatment. Hematin and heme arginate can shorten attacks and reduce the intensity of an attack but are not without side effects [5]

Carbohydrate restriction is not a factor in the common porphyria, porphyria cutanea tarda.

Question: does dietary heme as well as dietary glucose play a protective role in AIP and AVP?

[Edit: a first hand account of what it is like to have an undiagnosed porphyria - http://ahha.org/articles.asp?Id=119
Note it can be triggered by many common diet components including in this case corn fed to animals.
Beta carotene is an effective treatment for photosensitivity of acute variegate porphyria -
 http://www.rarediseasesnetwork.org/porphyrias/patients/treatment/index.htm ]

Systemic primary carnitine deficiency (SPCD) [6]

This syndrome, and others below, is almost certain to be diagnosed in infancy.

- also known as carnitine uptake defect, carnitine transporter deficiency (CTD) or systemic carnitine deficiency

- an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane.

- can be treated with high-dose l-carnitine supplementation

- although it is usually thought that MCTs do not require carnitine transport for beta-oxidation, tests with affected individuals have shown that MCTs are poorly metabolised in SPCD [7]

- Incidence: 1 per 100,000 except in Faroe Islands 1 per 1,000.

Other disorders that impair fatty acid oxidation and ketogenesis

A person with one of these disorders will have impaired metabolism of fatty acids when fasting, and will not produce ketones. Unless the condition is one treatable with l-carnitine, they may require a low-fat, high-carbohydrate diet.

Paradoxically a CPT1A defect is highly preserved in Arctic populations who evolved on a high-fat diet – this mutation suppresses ketosis and instead increases gluconeogenesis and heat generated from uncoupled fatty acid oxidation.[8]  The population of the Faroe Islands also traditionally ate a low-carbohydrate, high seafood diet; this would seem to suggest that CPT1A and perhaps SPCD defects are not true contraindications for such a diet.

Incomplete list of various fatty-acid metabolism disorders [9]

Carnitine Transporter Defect
Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Carnitine Palmitoyl Transferase I & II (CPT I & II) Deficiency
2,4 Dienoyl-CoA Reductase Deficiency
Electron Transfer Flavoprotein (ETF) Dehydrogenase Deficiency (GAII & MADD)
3-Hydroxy-3 Methylglutaryl-CoA Lyase (HMG) Deficiency
Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency)
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)
Short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD deficiency)
3-hydroxyacyl-coenzyme A dehydrogenase deficiency (M/SCHAD deficiency)

“Inborn errors in the enzymes involved in lipid metabolism: from mitochondrial membrane long-chain fatty acids transport mechanism to beta-oxidation and Krebs cycle could be potentially fatal during fasting or KDs. Thus, carnitine deficiency, carnitine palmitoyltransferase (CPT) I or II deficiency, carnitine translocase deficiency, b-oxidation defects, or pyruvate carboxylase deficiency should be screened before initiating the KD treatment.”[10] 

Note:  The most frequently occurring mitochondrial respiratory disorders impair glucose, rather than fatty acid oxidation and are identified as indications for ketogenic diets.[11]

[1] Acute variegate porphyria following a Scarsdale Gourmet Diet. Quiroz-Kendall E, Wilson FA, King LE Jr. J Am Acad Dermatol. 1983 Jan;8(1):46-9. PMID: 682680

[2] Acute intermittent porphyria presenting as acute pancreatitis and posterior reversible encephalopathy syndrome. Shen FC, Hsieh CH, Huang CR, et al. Acta Neurol Taiwan. 2008 Sep;17(3):177-83.

[3] A case of acute intermittent porphyria with acute pancreatitis. Shiraki K, Matsumoto H, Masuda T, et al. Gastroenterol Jpn. 1991 Feb;26(1):90-4.

[4] Acute intermittent porphyria with relapsing acute pancreatitis and unconjugated hyperbilirubinemia without overt hemolysis. Kobza K, Gyr K, Neuhaus K, Gudat F. Gastroenterology. 1976 Sep;71(3):494-6.

[5] Adapted from Wikipedia, retrieved 14/11/2014 http://en.wikipedia.org/wiki/Acute_intermittent_porphyria

[6] Systemic Primary Carnitine Deficiency. El-Hattab A W. http://www.ncbi.nlm.nih.gov/books/NBK84551/

[7] Medium-chain triglyceride loading test in carnitine-acylcarnitine translocase deficiency: insights on treatment. Parini R. et al. J Inherit Metab Dis. 1999 Aug;22(6):733-9. PMID: 10472533

[8] A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. Clemente F. J et al. American Journal of Human Genetics Volume 95, Issue 5, p584–589, 6 November 2014

[9] retrieved from Wikipedia 14/11/2014 http://en.wikipedia.org/wiki/Fatty-acid_metabolism_disorder

[10] Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases. Paoli, A. et al. BioMed Research International Volume 2014 (2014), Article ID 474296, 10 pages http://dx.doi.org/10.1155/2014/474296

[11] Safe and Effective Use of the Ketogenic Diet in Children with Epilepsy and Mitochondrial Respiratory Chain Complex Defects. Kang, H-C et al. 2006. Epilepsia, DOI: 10.1111/j.1528-1167.2006.00906.x

Compiled by George Henderson, Research Assistant, Human Potential Centre, Auckland University of Technology.

Any suggestions to improve this resource should be sent to the author at puddleg@gmail.com